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Li H, Rajani V, Sengar AS, Salter MW. Src dependency of the regulation of LTP by alternative splicing of GRIN1 exon 5. Philos Trans R Soc Lond B Biol Sci 2024; 379:20230236. [PMID: 38853562 PMCID: PMC11343231 DOI: 10.1098/rstb.2023.0236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 01/31/2024] [Accepted: 02/11/2024] [Indexed: 06/11/2024] Open
Abstract
Alternative splicing of Grin1 exon 5 regulates induction of long-term potentiation (LTP) at Schaffer collateral-CA1 synapses: LTP in mice lacking the GluN1 exon 5-encoded N1 cassette (GluN1a mice) is significantly increased compared with that in mice compulsorily expressing this exon (GluN1b mice). The mechanism underlying this difference is unknown. Here, we report that blocking the non-receptor tyrosine kinase Src prevents induction of LTP in GluN1a mice but not in GluN1b. We find that activating Src enhances pharmacologically isolated synaptic N-methyl-d-aspartate receptor (NMDAR) currents in GluN1a mice but not in GluN1b. Moreover, we observe that Src activation increases the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor component of Schaffer collateral-evoked excitatory post-synaptic potentials in GluN1a mice, but this increase is prevented by blocking NMDARs. We conclude that at these synapses, NMDARs in GluN1a mice are subject to upregulation by Src that mediates induction of LTP, whereas NMDARs in GluN1b mice are not regulated by Src, leading to Src-resistance of LTP. Thus, we have uncovered that a key regulatory mechanism for synaptic potentiation is gated by differential splicing of exon 5 of Grin1. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
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Affiliation(s)
- Hongbin Li
- Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ONM5G 1X8, Canada
| | - Vishaal Rajani
- Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ONM5G 1X8, Canada
| | - Ameet S. Sengar
- Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ONM5G 1X8, Canada
| | - Michael W. Salter
- Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ONM5G 1X8, Canada
- Department of Physiology, University of Toronto, Toronto, ONM5S 1A8, Canada
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Du R, Wang P, Tian N. CD3ζ-Mediated Signaling Protects Retinal Ganglion Cells in Glutamate Excitotoxicity of the Retina. Cells 2024; 13:1006. [PMID: 38920637 PMCID: PMC11201742 DOI: 10.3390/cells13121006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 05/28/2024] [Accepted: 06/06/2024] [Indexed: 06/27/2024] Open
Abstract
Excessive levels of glutamate activity could potentially damage and kill neurons. Glutamate excitotoxicity is thought to play a critical role in many CNS and retinal diseases. Accordingly, glutamate excitotoxicity has been used as a model to study neuronal diseases. Immune proteins, such as major histocompatibility complex (MHC) class I molecules and their receptors, play important roles in many neuronal diseases, while T-cell receptors (TCR) are the primary receptors of MHCI. We previously showed that a critical component of TCR, CD3ζ, is expressed by mouse retinal ganglion cells (RGCs). The mutation of CD3ζ or MHCI molecules compromises the development of RGC structure and function. In this study, we investigated whether CD3ζ-mediated molecular signaling regulates RGC death in glutamate excitotoxicity. We show that mutation of CD3ζ significantly increased RGC survival in NMDA-induced excitotoxicity. In addition, we found that several downstream molecules of TCR, including Src (proto-oncogene tyrosine-protein kinase) family kinases (SFKs) and spleen tyrosine kinase (Syk), are expressed by RGCs. Selective inhibition of an SFK member, Hck, or Syk members, Syk or Zap70, significantly increased RGC survival in NMDA-induced excitotoxicity. These results provide direct evidence to reveal the underlying molecular mechanisms that control RGC death under disease conditions.
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Affiliation(s)
- Rui Du
- Department of Ophthalmology and Visual Science, University of Utah School of Medicine, Salt Lake City, UT 84132, USA; (R.D.); (P.W.)
| | - Ping Wang
- Department of Ophthalmology and Visual Science, University of Utah School of Medicine, Salt Lake City, UT 84132, USA; (R.D.); (P.W.)
| | - Ning Tian
- Department of Ophthalmology and Visual Science, University of Utah School of Medicine, Salt Lake City, UT 84132, USA; (R.D.); (P.W.)
- Department of Neurobiology, University of Utah, Salt Lake City, UT 84132, USA
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84132, USA
- Veterans Affairs Medical Center, Salt Lake City, UT 84148, USA
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Pourhadi M, Zali H, Ghasemi R, Faizi M, Mojab F, Soufi Zomorrod M. Restoring Synaptic Function: How Intranasal Delivery of 3D-Cultured hUSSC Exosomes Improve Learning and Memory Deficits in Alzheimer's Disease. Mol Neurobiol 2024; 61:3724-3741. [PMID: 38010560 DOI: 10.1007/s12035-023-03733-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Accepted: 10/20/2023] [Indexed: 11/29/2023]
Abstract
Memory problems are often the first signs of cognitive impairment related to Alzheimer's disease (AD), and stem cells and stem cell-derived exosomes (EXOs) have been studied for their therapeutic potential to improve the disease signs. While many studies have shown the anti-inflammatory and immunomodulatory effects of stem cells and exosomes on improving memory in different AD models, there is still insufficient data to determine how they modulate neural plasticity to enhance spatial memory and learning ability. Therefore, we conducted a study to investigate the effects of exosomes derived from 3D-cultured human Unrestricted Somatic Stem Cells (hUSSCs) on spatial memory and neuroplasticity markers in a sporadic rat model of AD. Using male Wistar rats induced by intracerebral ventricle injection of streptozotocin, we demonstrated that intranasal administration of hUSSC-derived exosomes could decrease Aβ accumulation and improve learning and memory in the Morris water maze test. We also observed an increase in the expression of pre-synaptic and post-synaptic molecules involved in neuronal plasticity, including NMDAR1, integrin β1, synaptophysin, pPKCα, and GAP-43, in the hippocampus. Our findings suggest that intranasal administration of exosomes can ameliorate spatial learning and memory deficits in rats, at least in part, by increasing the expression of neuroplasticity proteins. These results may encourage researchers to further investigate the molecular pathways involved in memory improvement after stem cell and exosome therapy, with the goal of increasing the efficacy and safety of exosome-based treatments for AD.
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Affiliation(s)
- Masoumeh Pourhadi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hakimeh Zali
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Rasoul Ghasemi
- Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mehrdad Faizi
- Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Faraz Mojab
- Department of Pharmacognosy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mina Soufi Zomorrod
- Department of Hematology and Cell Therapy, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Nachtigall EG, de C Myskiw J, Izquierdo I, Furini CRG. Cellular mechanisms of contextual fear memory reconsolidation: Role of hippocampal SFKs, TrkB receptors and GluN2B-containing NMDA receptors. Psychopharmacology (Berl) 2024; 241:61-73. [PMID: 37700085 DOI: 10.1007/s00213-023-06463-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 08/31/2023] [Indexed: 09/14/2023]
Abstract
Memories are stored into long-term representations through a process that depends on protein synthesis. However, a consolidated memory is not static and inflexible and can be reactivated under certain circumstances, the retrieval is able to reactivate memories and destabilize them engaging a process of restabilization known as reconsolidation. Although the molecular mechanisms that mediate fear memory reconsolidation are not entirely known, so here we investigated the molecular mechanisms in the hippocampus involved in contextual fear conditioning memory (CFC) reconsolidation in male Wistar rats. We demonstrated that the blockade of Src family kinases (SFKs), GluN2B-containing NMDA receptors and TrkB receptors (TrkBR) in the CA1 region of the hippocampus immediately after the reactivation session impaired contextual fear memory reconsolidation. These impairments were blocked by the neurotrophin BDNF and the NMDAR agonist, D-Serine. Considering that the study of the link between synaptic proteins is crucial for understanding memory processes, targeting the reconsolidation process may provide new ways of disrupting maladaptive memories, such as those seen in post-traumatic stress disorder. Here we provide new insights into the cellular mechanisms involved in contextual fear memory reconsolidation, demonstrating that SFKs, GluN2B-containing NMDAR, and TrkBR are necessary for the reconsolidation process. Our findings suggest a link between BDNF and SFKs and GluN2B-containing NMDAR as well as a link between NMDAR and SFKs and TrkBR in fear memory reconsolidation. These preliminary pharmacological findings provide new evidence of the mechanisms involved in the reconsolidation of fear memory and have the potential to contribute to the development of treatments for psychiatric disorders involving maladaptive memories.
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Affiliation(s)
- Eduarda G Nachtigall
- Laboratory of Cognition and Memory Neurobiology, Brain Institute, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6690 - 3rd floor, Porto Alegre, RS, 90610-000, Brazil
- Memory Center, Brain Institute, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6690 - 2nd floor - HSL, Porto Alegre, RS, 90610-000, Brazil
| | - Jociane de C Myskiw
- Memory Center, Brain Institute, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6690 - 2nd floor - HSL, Porto Alegre, RS, 90610-000, Brazil
| | - Ivan Izquierdo
- Memory Center, Brain Institute, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6690 - 2nd floor - HSL, Porto Alegre, RS, 90610-000, Brazil
| | - Cristiane R G Furini
- Laboratory of Cognition and Memory Neurobiology, Brain Institute, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6690 - 3rd floor, Porto Alegre, RS, 90610-000, Brazil.
- Memory Center, Brain Institute, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6690 - 2nd floor - HSL, Porto Alegre, RS, 90610-000, Brazil.
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Samhan-Arias AK, Poejo J, Marques-da-Silva D, Martínez-Costa OH, Gutierrez-Merino C. Are There Lipid Membrane-Domain Subtypes in Neurons with Different Roles in Calcium Signaling? Molecules 2023; 28:7909. [PMID: 37894616 PMCID: PMC10708093 DOI: 10.3390/molecules28237909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 11/24/2023] [Accepted: 11/29/2023] [Indexed: 12/18/2023] Open
Abstract
Lipid membrane nanodomains or lipid rafts are 10-200 nm diameter size cholesterol- and sphingolipid-enriched domains of the plasma membrane, gathering many proteins with different roles. Isolation and characterization of plasma membrane proteins by differential centrifugation and proteomic studies have revealed a remarkable diversity of proteins in these domains. The limited size of the lipid membrane nanodomain challenges the simple possibility that all of them can coexist within the same lipid membrane domain. As caveolin-1, flotillin isoforms and gangliosides are currently used as neuronal lipid membrane nanodomain markers, we first analyzed the structural features of these components forming nanodomains at the plasma membrane since they are relevant for building supramolecular complexes constituted by these molecular signatures. Among the proteins associated with neuronal lipid membrane nanodomains, there are a large number of proteins that play major roles in calcium signaling, such as ionotropic and metabotropic receptors for neurotransmitters, calcium channels, and calcium pumps. This review highlights a large variation between the calcium signaling proteins that have been reported to be associated with isolated caveolin-1 and flotillin-lipid membrane nanodomains. Since these calcium signaling proteins are scattered in different locations of the neuronal plasma membrane, i.e., in presynapses, postsynapses, axonal or dendritic trees, or in the neuronal soma, our analysis suggests that different lipid membrane-domain subtypes should exist in neurons. Furthermore, we conclude that classification of lipid membrane domains by their content in calcium signaling proteins sheds light on the roles of these domains for neuronal activities that are dependent upon the intracellular calcium concentration. Some examples described in this review include the synaptic and metabolic activity, secretion of neurotransmitters and neuromodulators, neuronal excitability (long-term potentiation and long-term depression), axonal and dendritic growth but also neuronal cell survival and death.
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Affiliation(s)
- Alejandro K. Samhan-Arias
- Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), C/Arturo Duperier 4, 28029 Madrid, Spain;
- Instituto de Investigaciones Biomédicas ‘Sols-Morreale’ (CSIC-UAM), C/Arturo Duperier 4, 28029 Madrid, Spain
| | - Joana Poejo
- Instituto de Biomarcadores de Patologías Moleculares, Universidad de Extremadura, 06006 Badajoz, Spain;
| | - Dorinda Marques-da-Silva
- LSRE—Laboratory of Separation and Reaction Engineering and LCM—Laboratory of Catalysis and Materials, School of Management and Technology, Polytechnic Institute of Leiria, Morro do Lena-Alto do Vieiro, 2411-901 Leiria, Portugal;
- ALiCE—Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal
- School of Technology and Management, Polytechnic Institute of Leiria, Morro do Lena-Alto do Vieiro, 2411-901 Leiria, Portugal
| | - Oscar H. Martínez-Costa
- Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), C/Arturo Duperier 4, 28029 Madrid, Spain;
- Instituto de Investigaciones Biomédicas ‘Sols-Morreale’ (CSIC-UAM), C/Arturo Duperier 4, 28029 Madrid, Spain
| | - Carlos Gutierrez-Merino
- Instituto de Biomarcadores de Patologías Moleculares, Universidad de Extremadura, 06006 Badajoz, Spain;
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Jiang Y, Li L, Wu R, Wu L, Zhang B, Wang JZ, Liu R, Liu F, Wang J, Wang X. c-Src regulates δ-secretase activation and truncated Tau production by phosphorylating the E3 ligase Traf6. J Biol Chem 2023; 299:105462. [PMID: 37977223 PMCID: PMC10711223 DOI: 10.1016/j.jbc.2023.105462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 10/31/2023] [Accepted: 11/05/2023] [Indexed: 11/19/2023] Open
Abstract
The accumulation of abnormal Tau protein is a common feature of various neurodegenerative diseases. Truncated Tau, resulting from cleavage by asparaginyl endopeptidase (AEP, δ-secretase), promotes its own phosphorylation and aggregation. Our study focused on understanding the regulatory mechanisms of AEP activation and its interaction with other proteins. We discovered that c-Src plays a critical role in mediating the activation and polyubiquitination of AEP in response to epidermal growth factor stimulation. In addition, we investigated the involvement of tumor necrosis factor receptor-associated factor 6 (Traf6), an E3 ligase, in the regulation of AEP levels and its interaction with c-Src. Knockdown of Traf6 effectively inhibited c-Src-induced AEP activation. To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src. By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation. Pharmacological inhibition of c-Src reduced the phosphorylation of Traf6 and inhibited AEP activation in neurons derived from human-induced pluripotent stem cells. Conditional knockout of Traf6 in neurons prevented c-Src-induced AEP activation and subsequent Tau truncation in vivo. Moreover, phosphorylation of Traf6 is highly correlated with AEP activation, Tau368 and pathological Tau (AT8) in Alzheimer's disease brain. Overall, our study elucidates the role of c-Src in regulating AEP-cleaved Tau through phosphorylating Traf6. Targeting the c-Src-Traf6 pathway may hold potential for the treatment of Alzheimer's disease and other tauopathies.
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Affiliation(s)
- Yanli Jiang
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Longfei Li
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ruozhen Wu
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liulin Wu
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bin Zhang
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian-Zhi Wang
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China
| | - Rong Liu
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fei Liu
- Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, USA.
| | - Jing Wang
- Department of Immunology School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Xiaochuan Wang
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China; Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, China.
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Wu XL, Yan QJ, Zhu F. Abnormal synaptic plasticity and impaired cognition in schizophrenia. World J Psychiatry 2022; 12:541-557. [PMID: 35582335 PMCID: PMC9048451 DOI: 10.5498/wjp.v12.i4.541] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 07/28/2021] [Accepted: 03/27/2022] [Indexed: 02/06/2023] Open
Abstract
Schizophrenia (SCZ) is a severe mental illness that affects several brain domains with relation to cognition and behaviour. SCZ symptoms are typically classified into three categories, namely, positive, negative, and cognitive. The etiology of SCZ is thought to be multifactorial and poorly understood. Accumulating evidence has indicated abnormal synaptic plasticity and cognitive impairments in SCZ. Synaptic plasticity is thought to be induced at appropriate synapses during memory formation and has a critical role in the cognitive symptoms of SCZ. Many factors, including synaptic structure changes, aberrant expression of plasticity-related genes, and abnormal synaptic transmission, may influence synaptic plasticity and play vital roles in SCZ. In this article, we briefly summarize the morphology of the synapse, the neurobiology of synaptic plasticity, and the role of synaptic plasticity, and review potential mechanisms underlying abnormal synaptic plasticity in SCZ. These abnormalities involve dendritic spines, postsynaptic density, and long-term potentiation-like plasticity. We also focus on cognitive dysfunction, which reflects impaired connectivity in SCZ. Additionally, the potential targets for the treatment of SCZ are discussed in this article. Therefore, understanding abnormal synaptic plasticity and impaired cognition in SCZ has an essential role in drug therapy.
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Affiliation(s)
- Xiu-Lin Wu
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Qiu-Jin Yan
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Fan Zhu
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
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Kato G. Regulatory Roles of the N-Terminal Intrinsically Disordered Region of Modular Src. Int J Mol Sci 2022; 23:2241. [PMID: 35216357 PMCID: PMC8874404 DOI: 10.3390/ijms23042241] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 02/15/2022] [Accepted: 02/15/2022] [Indexed: 11/17/2022] Open
Abstract
Src, the prototype of Src family kinases (SFKs), is a modular protein consisting of SH4 (SH4) and unique (UD) domains in an N-terminal intrinsically disordered region (IDR), and SH3, SH2, and kinase (KD) folded domains conserved among SFKs. Src functions as a pleiotropic signaling hub in proliferating and post-mitotic cells, and it is related to cancer and neurological diseases. However, its regulatory mechanism is unclear because the existing canonical model is derived from crystallographic analyses of folded constructs lacking the IDR. This work reviews nuclear magnetic resonance analyses of partially structured lipid-binding segments in the flexible UD and the fuzzy intramolecular complex (FIMC) comprising IDR and SH3 domains, which interacts with lipid membranes and proteins. Furthermore, recently determined IDR-related Src characteristics are discussed, including dimerization, SH4/KD intramolecular fastener bundling of folded domains, and the sorting of adhesive structures. Finally, the modulatory roles of IDR phosphorylation in Src activities involving the FIMC are explored. The new regulatory roles of IDRs are integrated with the canonical model to elucidate the functions of full-length Src. This review presents new aspects of Src regulation, and provides a future direction for studies on the structure and function of Src, and their implications for pathological processes.
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Affiliation(s)
- Goro Kato
- Laboratory of Biological Chemistry, Center for Medical Education and Sciences, University of Yamanashi, 1110 Shimokato, Chuo 409-3898, Yamanashi, Japan
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Le AA, Quintanilla J, Amani M, Piomelli D, Lynch G, Gall CM. Persistent sexually dimorphic effects of adolescent THC exposure on hippocampal synaptic plasticity and episodic memory in rodents. Neurobiol Dis 2022; 162:105565. [PMID: 34838664 DOI: 10.1016/j.nbd.2021.105565] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 10/04/2021] [Accepted: 11/23/2021] [Indexed: 01/01/2023] Open
Abstract
There is evidence that cannabis use during adolescence leads to memory and cognitive problems in young adulthood but little is known about effects of early life cannabis exposure on synaptic operations that are critical for encoding and organizing information. We report here that a 14-day course of daily Δ9-tetrahydrocannabinol treatments administered to adolescent rats and mice (aTHC) leads to profound but selective deficits in synaptic plasticity in two axonal systems in female, and to lesser extent male, hippocampus as assessed in adulthood. Adolescent-THC exposure did not alter basic synaptic transmission (input/output curves) and had only modest effects on frequency facilitation. Nevertheless, aTHC severely impaired the endocannabinoid-dependent long-term potentiation in the lateral perforant path in females of both species, and in male mice; this was reliably associated with impaired acquisition of a component of episodic memory that depends on lateral perforant path function. Potentiation in the Schaffer-commissural (S-C) projection to field CA1 was disrupted by aTHC treatment in females only and this was associated with both a deficit in estrogen effects on S-C synaptic responses and impairments to CA1-dependent spatial (object location) memory. In all the results demonstrate sexually dimorphic and projection system-specific effects of aTHC exposure that could underlie discrete effects of early life cannabinoid usage on adult cognitive function. Moreover they suggest that some of the enduring, sexually dimorphic effects of cannabis use reflect changes in synaptic estrogen action.
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Affiliation(s)
- Aliza A Le
- Departments of Anatomy & Neurobiology, University of California, Irvine, CA 92697, United States of America
| | - Julian Quintanilla
- Departments of Anatomy & Neurobiology, University of California, Irvine, CA 92697, United States of America
| | - Mohammad Amani
- Departments of Anatomy & Neurobiology, University of California, Irvine, CA 92697, United States of America
| | - Daniele Piomelli
- Departments of Anatomy & Neurobiology, University of California, Irvine, CA 92697, United States of America
| | - Gary Lynch
- Departments of Anatomy & Neurobiology, University of California, Irvine, CA 92697, United States of America; Departments of Psychiatry & Human Behavior, University of California, Irvine, CA 92868, United States of America.
| | - Christine M Gall
- Departments of Anatomy & Neurobiology, University of California, Irvine, CA 92697, United States of America; Departments of Neurobiology & Behavior, University of California, Irvine, CA 92697, United States of America.
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10
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de Pins B, Mendes T, Giralt A, Girault JA. The Non-receptor Tyrosine Kinase Pyk2 in Brain Function and Neurological and Psychiatric Diseases. Front Synaptic Neurosci 2021; 13:749001. [PMID: 34690733 PMCID: PMC8527176 DOI: 10.3389/fnsyn.2021.749001] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 09/14/2021] [Indexed: 12/28/2022] Open
Abstract
Pyk2 is a non-receptor tyrosine kinase highly enriched in forebrain neurons. Pyk2 is closely related to focal adhesion kinase (FAK), which plays an important role in sensing cell contacts with extracellular matrix and other extracellular signals controlling adhesion and survival. Pyk2 shares some of FAK’s characteristics including recruitment of Src-family kinases after autophosphorylation, scaffolding by interacting with multiple partners, and activation of downstream signaling pathways. Pyk2, however, has the unique property to respond to increases in intracellular free Ca2+, which triggers its autophosphorylation following stimulation of various receptors including glutamate NMDA receptors. Pyk2 is dephosphorylated by the striatal-enriched phosphatase (STEP) that is highly expressed in the same neuronal populations. Pyk2 localization in neurons is dynamic, and altered following stimulation, with post-synaptic and nuclear enrichment. As a signaling protein Pyk2 is involved in multiple pathways resulting in sometimes opposing functions depending on experimental models. Thus Pyk2 has a dual role on neurites and dendritic spines. With Src family kinases Pyk2 participates in postsynaptic regulations including of NMDA receptors and is necessary for specific types of synaptic plasticity and spatial memory tasks. The diverse functions of Pyk2 are also illustrated by its role in pathology. Pyk2 is activated following epileptic seizures or ischemia-reperfusion and may contribute to the consequences of these insults whereas Pyk2 deficit may contribute to the hippocampal phenotype of Huntington’s disease. Pyk2 gene, PTK2B, is associated with the risk for late-onset Alzheimer’s disease. Studies of underlying mechanisms indicate a complex contribution with involvement in amyloid toxicity and tauopathy, combined with possible functional deficits in neurons and contribution in microglia. A role of Pyk2 has also been proposed in stress-induced depression and cocaine addiction. Pyk2 is also important for the mobility of astrocytes and glioblastoma cells. The implication of Pyk2 in various pathological conditions supports its potential interest for therapeutic interventions. This is possible through molecules inhibiting its activity or increasing it through inhibition of STEP or other means, depending on a precise evaluation of the balance between positive and negative consequences of Pyk2 actions.
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Affiliation(s)
- Benoit de Pins
- Institut du Fer à Moulin, Paris, France.,Inserm UMR-S 1270, Paris, France.,Faculté des Sciences et Ingénierie, Sorbonne Université, Paris, France
| | - Tiago Mendes
- Institut du Fer à Moulin, Paris, France.,Inserm UMR-S 1270, Paris, France.,Faculté des Sciences et Ingénierie, Sorbonne Université, Paris, France
| | - Albert Giralt
- Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.,Production and Validation Center of Advanced Therapies (Creatio), Faculty of Medicine and Health Science, University of Barcelona, Barcelona, Spain
| | - Jean-Antoine Girault
- Institut du Fer à Moulin, Paris, France.,Inserm UMR-S 1270, Paris, France.,Faculté des Sciences et Ingénierie, Sorbonne Université, Paris, France
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11
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Rajani V, Sengar AS, Salter MW. Src and Fyn regulation of NMDA receptors in health and disease. Neuropharmacology 2021; 193:108615. [PMID: 34051267 DOI: 10.1016/j.neuropharm.2021.108615] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/10/2021] [Accepted: 05/12/2021] [Indexed: 11/28/2022]
Abstract
The Src family kinases (SFKs) are cytoplasmic non-receptor tyrosine kinases involved in multiple signalling pathways. In the central nervous system (CNS), SFKs are key regulators of N-methyl-d-aspartate receptor (NMDAR) function and major points of convergence for neuronal transduction pathways. Physiological upregulation of NMDAR activity by members of the SFKs, namely Src and Fyn, is crucial for induction of plasticity at Schaffer collateral-CA1 synapses of the hippocampus. Aberrant SFK regulation of NMDARs is implicated in several pathological conditions in the CNS including schizophrenia and pain hypersensitivity. Here, evidence is presented to highlight the current understanding of the intermolecular interactions of SFKs within the NMDAR macromolecular complex, the upstream regulators of SFK activity on NMDAR function and the role Src and Fyn have in synaptic plasticity and metaplasticity. The targeting of SFK protein-protein interactions is discussed as a potential therapeutic strategy to restore signalling activity underlying glutamatergic dysregulation in CNS disease pathophysiology.
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Affiliation(s)
- Vishaal Rajani
- Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, A1B 3V6, Canada; Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada
| | - Ameet S Sengar
- Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada
| | - Michael W Salter
- Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
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12
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Sengar AS, Li H, Zhang W, Leung C, Ramani AK, Saw NM, Wang Y, Tu Y, Ross PJ, Scherer SW, Ellis J, Brudno M, Jia Z, Salter MW. Control of Long-Term Synaptic Potentiation and Learning by Alternative Splicing of the NMDA Receptor Subunit GluN1. Cell Rep 2020; 29:4285-4294.e5. [PMID: 31875540 DOI: 10.1016/j.celrep.2019.11.087] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 10/05/2019] [Accepted: 11/21/2019] [Indexed: 01/09/2023] Open
Abstract
NMDA receptors (NMDARs) are critical for physiological synaptic plasticity, learning, and memory and for pathological plasticity and neuronal death. The GluN1 subunit is encoded by a single gene, GRIN1, with 8 splice variants, but whether the diversity generated by this splicing has physiological consequences remains enigmatic. Here, we generate mice lacking from the GluN1 exon 5-encoded N1 cassette (GluN1a mice) or compulsorily expressing this exon (GluN1b mice). Despite no differences in basal synaptic transmission, long-term potentiation in the hippocampus is significantly enhanced in GluN1a mice compared with that in GluN1b mice. Furthermore, GluN1a mice learn more quickly and have significantly better spatial memory performance than do GluN1b mice. In addition, in human iPSC-derived neurons in autism spectrum disorder NMDARs show characteristics of N1-lacking GluN1. Our findings indicate that alternative splicing of GluN1 is a mechanism for controlling physiological long-lasting synaptic potentiation, learning, and memory.
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Affiliation(s)
- Ameet S Sengar
- Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Hongbin Li
- Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Wenbo Zhang
- Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Celeste Leung
- Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Arun K Ramani
- Centre for Computational Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Ner Mu Saw
- Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Yongqian Wang
- Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - YuShan Tu
- Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - P Joel Ross
- Biology Department, University of Prince Edward Island, Charlottetown, PE C1A 4P3, Canada
| | - Stephen W Scherer
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; McLaughlin Centre, University of Toronto, Toronto, ON M5G 0A4, Canada
| | - James Ellis
- Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Michael Brudno
- Centre for Computational Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5T 3A1, Canada
| | - Zhengping Jia
- Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Michael W Salter
- Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
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13
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Felix L, Delekate A, Petzold GC, Rose CR. Sodium Fluctuations in Astroglia and Their Potential Impact on Astrocyte Function. Front Physiol 2020; 11:871. [PMID: 32903427 PMCID: PMC7435049 DOI: 10.3389/fphys.2020.00871] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 06/29/2020] [Indexed: 12/12/2022] Open
Abstract
Astrocytes are the main cell type responsible for the regulation of brain homeostasis, including the maintenance of ion gradients and neurotransmitter clearance. These processes are tightly coupled to changes in the intracellular sodium (Na+) concentration. While activation of the sodium-potassium-ATPase (NKA) in response to an elevation of extracellular K+ may decrease intracellular Na+, the cotransport of transmitters, such as glutamate, together with Na+ results in an increase in astrocytic Na+. This increase in intracellular Na+ can modulate, for instance, metabolic downstream pathways. Thereby, astrocytes are capable to react on a fast time scale to surrounding neuronal activity via intracellular Na+ fluctuations and adjust energy production to the demand of their environment. Beside the well-documented conventional roles of Na+ signaling mainly mediated through changes in its electrochemical gradient, several recent studies have identified more atypical roles for Na+, including protein interactions leading to changes in their biochemical activity or Na+-dependent regulation of gene expression. In this review, we will address both the conventional as well as the atypical functions of astrocytic Na+ signaling, presenting the role of transporters and channels involved and their implications for physiological processes in the central nervous system (CNS). We will also discuss how these important functions are affected under pathological conditions, including stroke and migraine. We postulate that Na+ is an essential player not only in the maintenance of homeostatic processes but also as a messenger for the fast communication between neurons and astrocytes, adjusting the functional properties of various cellular interaction partners to the needs of the surrounding network.
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Affiliation(s)
- Lisa Felix
- Institute of Neurobiology, Heinrich Heine University Duesseldorf, Duesseldorf, Germany
| | - Andrea Delekate
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - Gabor C Petzold
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.,Division of Vascular Neurology, Department of Neurology, University Hospital Bonn, Bonn, Germany
| | - Christine R Rose
- Institute of Neurobiology, Heinrich Heine University Duesseldorf, Duesseldorf, Germany
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14
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Westlund KN, Lu Y, Zhang L, Pappas TC, Zhang WR, Taglialatela G, McIlwrath SL, McNearney TA. Tyrosine Kinase Inhibitors Reduce NMDA NR1 Subunit Expression, Nuclear Translocation, and Behavioral Pain Measures in Experimental Arthritis. Front Physiol 2020; 11:440. [PMID: 32536874 PMCID: PMC7267073 DOI: 10.3389/fphys.2020.00440] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 04/08/2020] [Indexed: 11/17/2022] Open
Abstract
In the lumbar spinal cord dorsal horn, release of afferent nerve glutamate activates the neurons that relay information about injury pain. Here, we examined the effects of protein tyrosine kinase (PTK) inhibition on NMDA receptor NR1 subunit protein expression and subcellular localization in an acute experimental arthritis model. PTK inhibitors genistein and lavendustin A reduced cellular histological translocation of NMDA NR1 in the spinal cord occurring after the inflammatory insult and the nociceptive behavioral responses to heat. The PTK inhibitors were administered into lumbar spinal cord by microdialysis, and secondary heat hyperalgesia was determined using the Hargreaves test. NMDA NR1 cellular protein expression and nuclear translocation were determined by immunocytochemical localization with light and electron microscopy, as well as with Western blot analysis utilizing both C- and N-terminal antibodies. Genistein and lavendustin A (but not inactive lavendustin B or diadzein) effectively reduced (i) pain related behavior, (ii) NMDA NR1 subunit expression increases in spinal cord, and (iii) the shift of NR1 from a cell membrane to a nuclear localization. Genistein pre-treatment reduced these events that occur in vivo within 4 h after inflammatory insult to the knee joint with kaolin and carrageenan (k/c). Cycloheximide reduced glutamate activated upregulation of NR1 content confirming synthesis of new protein in response to the inflammatory insult. In addition to this in vivo data, genistein or staurosporin inhibited upregulation of NMDA NR1 protein and nuclear translocation in vitro after treatment of human neuroblastoma clonal cell cultures (SH-SY5Y) with glutamate or NMDA (4 h). These studies provide evidence that inflammatory activation of peripheral nerves initiates increase in NMDA NR1 in the spinal cord coincident with development of pain related behaviors through glutamate non-receptor, PTK dependent cascades.
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Affiliation(s)
- Karin N Westlund
- Research Division, New Mexico VA Health Care System, Albuquerque, NM, United States.,Anesthesiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States.,Neuroscience and Cell Biology, University of Texas Medical Branch at Galveston, Galveston, TX, United States
| | - Ying Lu
- Neuroscience and Cell Biology, University of Texas Medical Branch at Galveston, Galveston, TX, United States
| | - Liping Zhang
- Neuroscience and Cell Biology, University of Texas Medical Branch at Galveston, Galveston, TX, United States
| | - Todd C Pappas
- Neuroscience and Cell Biology, University of Texas Medical Branch at Galveston, Galveston, TX, United States
| | - Wen-Ru Zhang
- Neuroscience and Cell Biology, University of Texas Medical Branch at Galveston, Galveston, TX, United States
| | - Giulio Taglialatela
- Neuroscience and Cell Biology, University of Texas Medical Branch at Galveston, Galveston, TX, United States.,Neurology, University of Texas Medical Branch at Galveston, Galveston, TX, United States
| | - Sabrina L McIlwrath
- Research Division, New Mexico VA Health Care System, Albuquerque, NM, United States
| | - Terry A McNearney
- Neuroscience and Cell Biology, University of Texas Medical Branch at Galveston, Galveston, TX, United States.,Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX, United States.,Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, TX, United States
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15
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Brzdak P, Wójcicka O, Zareba-Koziol M, Minge D, Henneberger C, Wlodarczyk J, Mozrzymas JW, Wójtowicz T. Synaptic Potentiation at Basal and Apical Dendrites of Hippocampal Pyramidal Neurons Involves Activation of a Distinct Set of Extracellular and Intracellular Molecular Cues. Cereb Cortex 2020; 29:283-304. [PMID: 29228131 DOI: 10.1093/cercor/bhx324] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 11/07/2017] [Indexed: 12/12/2022] Open
Abstract
In the central nervous system, several forms of experience-dependent plasticity, learning and memory require the activity-dependent control of synaptic efficacy. Despite substantial progress in describing synaptic plasticity, mechanisms related to heterogeneity of synaptic functions at local circuits remain elusive. Here we studied the functional and molecular aspects of hippocampal circuit plasticity by analyzing excitatory synapses at basal and apical dendrites of mouse hippocampal pyramidal cells (CA1 region) in acute brain slices. In the past decade, activity of metalloproteinases (MMPs) has been implicated as a widespread and critical factor in plasticity mechanisms at various projections in the CNS. However, in the present study we discovered that in striking contrast to apical dendrites, synapses located within basal dendrites undergo MMP-independent synaptic potentiation. We demonstrate that synapse-specific molecular pathway allowing MMPs to rapidly upregulate function of NMDARs in stratum radiatum involved protease activated receptor 1 and intracellular kinases and GTPases activity. In contrast, MMP-independent scaling of synaptic strength in stratum oriens involved dopamine D1/D5 receptors and Src kinases. Results of this study reveal that 2 neighboring synaptic systems differ significantly in extracellular and intracellular cascades that control synaptic gain and provide long-searched transduction pathways relevant for MMP-dependent synaptic plasticity.
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Affiliation(s)
- Patrycja Brzdak
- Laboratory of Neuroscience, Department of Biophysics, Wroclaw Medical University, Wroclaw, Poland.,Department of Molecular Physiology and Neurobiology, Wroclaw University, Wroclaw, Poland
| | - Olga Wójcicka
- Laboratory of Neuroscience, Department of Biophysics, Wroclaw Medical University, Wroclaw, Poland
| | - Monika Zareba-Koziol
- Laboratory of Cell Biophysics, Department of Molecular and Cellular Neurobiology, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Daniel Minge
- Institute of Cellular Neurosciences, University of Bonn Medical School, Bonn, Germany
| | - Christian Henneberger
- Institute of Cellular Neurosciences, University of Bonn Medical School, Bonn, Germany.,Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.,Institute of Neurology, University College London, London, UK
| | - Jakub Wlodarczyk
- Laboratory of Cell Biophysics, Department of Molecular and Cellular Neurobiology, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Jerzy W Mozrzymas
- Laboratory of Neuroscience, Department of Biophysics, Wroclaw Medical University, Wroclaw, Poland.,Department of Molecular Physiology and Neurobiology, Wroclaw University, Wroclaw, Poland
| | - Tomasz Wójtowicz
- Laboratory of Neuroscience, Department of Biophysics, Wroclaw Medical University, Wroclaw, Poland
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16
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Brown AS, Meera P, Quinones G, Magri J, Otis TS, Pulst SM, Oro AE. Receptor protein tyrosine phosphatases control Purkinje neuron firing. Cell Cycle 2020; 19:153-159. [PMID: 31876231 PMCID: PMC6961678 DOI: 10.1080/15384101.2019.1695995] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 10/23/2019] [Accepted: 11/07/2019] [Indexed: 10/25/2022] Open
Abstract
Spinocerebellar ataxias (SCA) are a genetically heterogeneous family of cerebellar neurodegenerative diseases characterized by abnormal firing of Purkinje neurons and degeneration. We recently demonstrated the slowed firing rates seen in several SCAs share a common etiology of hyper-activation of the Src family of non-receptor tyrosine kinases (SFKs). However, the lack of clinically available neuroactive SFK inhibitors lead us to investigate alternative mechanisms to modulate SFK activity. Previous studies demonstrate that SFK activity can be enhanced by the removal of inhibitory phospho-marks by receptor-protein-tyrosine phosphatases (RPTPs). In this Extra View we show that MTSS1 inhibits SFK activity through the binding and inhibition of a subset of the RPTP family members, and lowering RPTP activity in cerebellar slices with peptide inhibitors increases the suppressed Purkinje neuron basal firing rates seen in two different SCA models. Together these results identify RPTPs as novel effectors of Purkinje neuron basal firing, extending the MTSS1/SFK regulatory circuit we previously described and expanding the therapeutic targets for SCA patients.
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Affiliation(s)
- Alexander S. Brown
- Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA
| | - Pratap Meera
- Department of Neurobiology, University of California, Los Angeles, CA, USA
| | - Gabe Quinones
- Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA
| | - Jessica Magri
- Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA
| | - Thomas S. Otis
- Sainsbury Wellcome Centre for Neural Circuits and Behavior, University College London, London, UK
| | - Stefan M. Pulst
- Department of Neurology, University of Utah Medical Center, Salt Lake City, UT, USA
| | - Anthony E. Oro
- Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA
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17
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Harde E, Nicholson L, Furones Cuadrado B, Bissen D, Wigge S, Urban S, Segarra M, Ruiz de Almodóvar C, Acker-Palmer A. EphrinB2 regulates VEGFR2 during dendritogenesis and hippocampal circuitry development. eLife 2019; 8:49819. [PMID: 31868584 PMCID: PMC6927743 DOI: 10.7554/elife.49819] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 11/06/2019] [Indexed: 12/12/2022] Open
Abstract
Vascular endothelial growth factor (VEGF) is an angiogenic factor that play important roles in the nervous system, although it is still unclear which receptors transduce those signals in neurons. Here, we show that in the developing hippocampus VEGFR2 (also known as KDR or FLK1) is expressed specifically in the CA3 region and it is required for dendritic arborization and spine morphogenesis in hippocampal neurons. Mice lacking VEGFR2 in neurons (Nes-cre Kdrlox/-) show decreased dendritic arbors and spines as well as a reduction in long-term potentiation (LTP) at the associational-commissural – CA3 synapses. Mechanistically, VEGFR2 internalization is required for VEGF-induced spine maturation. In analogy to endothelial cells, ephrinB2 controls VEGFR2 internalization in neurons. VEGFR2-ephrinB2 compound mice (Nes-cre Kdrlox/+ Efnb2lox/+) show reduced dendritic branching, reduced spine head size and impaired LTP. Our results demonstrate the functional crosstalk of VEGFR2 and ephrinB2 in vivo to control dendritic arborization, spine morphogenesis and hippocampal circuitry development.
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Affiliation(s)
- Eva Harde
- Institute of Cell Biology and Neuroscience, University of Frankfurt, Frankfurt, Germany.,Max Planck Institute for Brain Research, Frankfurt, Germany.,Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Frankfurt, Germany
| | - LaShae Nicholson
- Institute of Cell Biology and Neuroscience, University of Frankfurt, Frankfurt, Germany.,Max Planck Institute for Brain Research, Frankfurt, Germany.,Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Frankfurt, Germany
| | - Beatriz Furones Cuadrado
- Institute of Cell Biology and Neuroscience, University of Frankfurt, Frankfurt, Germany.,Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Frankfurt, Germany
| | - Diane Bissen
- Institute of Cell Biology and Neuroscience, University of Frankfurt, Frankfurt, Germany.,Max Planck Institute for Brain Research, Frankfurt, Germany.,Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Frankfurt, Germany
| | - Sylvia Wigge
- Institute of Cell Biology and Neuroscience, University of Frankfurt, Frankfurt, Germany.,Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Frankfurt, Germany
| | - Severino Urban
- Biochemistry Center (BZH), Heidelberg University, Heidelberg, Germany
| | - Marta Segarra
- Institute of Cell Biology and Neuroscience, University of Frankfurt, Frankfurt, Germany.,Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Frankfurt, Germany
| | - Carmen Ruiz de Almodóvar
- Biochemistry Center (BZH), Heidelberg University, Heidelberg, Germany.,European Center for Angioscience, Medicine Faculty Mannheim, Heidelberg University, Heidelberg, Germany.,Institute for Transfusion Medicine and Immunology, Medicine Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - Amparo Acker-Palmer
- Institute of Cell Biology and Neuroscience, University of Frankfurt, Frankfurt, Germany.,Max Planck Institute for Brain Research, Frankfurt, Germany.,Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Frankfurt, Germany.,Cardio-Pulmonary Institute (CPI), Frankfurt, Germany
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18
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Backlund CM, Hango CR, Minter LM, Tew GN. Protein and Antibody Delivery into Difficult-to-Transfect Cells by Polymeric Peptide Mimics. ACS APPLIED BIO MATERIALS 2019; 3:180-185. [DOI: 10.1021/acsabm.9b00876] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Coralie M. Backlund
- Department of Polymer Science & Engineering, University of Massachusetts, Amherst, Massachusetts 01003, United States
| | - Christopher R. Hango
- Department of Polymer Science & Engineering, University of Massachusetts, Amherst, Massachusetts 01003, United States
| | - Lisa M. Minter
- Molecular and Cellular Biology Program, University of Massachusetts, Amherst, Massachusetts 01003, United States
- Department of Veterinary & Animal Sciences, University of Massachusetts, Amherst, Massachusetts 01003, Untied States
| | - Gregory N. Tew
- Department of Polymer Science & Engineering, University of Massachusetts, Amherst, Massachusetts 01003, United States
- Molecular and Cellular Biology Program, University of Massachusetts, Amherst, Massachusetts 01003, United States
- Department of Veterinary & Animal Sciences, University of Massachusetts, Amherst, Massachusetts 01003, Untied States
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19
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Latent Sex Differences in Molecular Signaling That Underlies Excitatory Synaptic Potentiation in the Hippocampus. J Neurosci 2018; 39:1552-1565. [PMID: 30578341 DOI: 10.1523/jneurosci.1897-18.2018] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 11/27/2018] [Accepted: 12/13/2018] [Indexed: 01/25/2023] Open
Abstract
Excitatory synapses can be potentiated by chemical neuromodulators, including 17β-estradiol (E2), or patterns of synaptic activation, as in long-term potentiation (LTP). Here, we investigated kinases and calcium sources required for acute E2-induced synaptic potentiation in the hippocampus of each sex and tested whether sex differences in kinase signaling extend to LTP. We recorded EPSCs from CA1 pyramidal cells in hippocampal slices from adult rats and used specific inhibitors of kinases and calcium sources. This revealed that, although E2 potentiates synapses to the same degree in each sex, cAMP-activated protein kinase (PKA) is required to initiate potentiation only in females. In contrast, mitogen-activated protein kinase, Src tyrosine kinase, and rho-associated kinase are required for initiation in both sexes; similarly, Ca2+/calmodulin-activated kinase II is required for expression/maintenance of E2-induced potentiation in both sexes. Calcium source experiments showed that L-type calcium channels and calcium release from internal stores are both required for E2-induced potentiation in females, whereas in males, either L-type calcium channel activation or calcium release from stores is sufficient to permit potentiation. To investigate the generalizability of a sex difference in the requirement for PKA in synaptic potentiation, we tested how PKA inhibition affects LTP. This showed that, although the magnitude of both high-frequency stimulation-induced and pairing-induced LTP is the same between sexes, PKA is required for LTP in females but not males. These results demonstrate latent sex differences in mechanisms of synaptic potentiation in which distinct molecular signaling converges to common functional endpoints in males and females.SIGNIFICANCE STATEMENT Chemical- and activity-dependent neuromodulation alters synaptic strength in both male and female brains, yet few studies have compared mechanisms of neuromodulation between the sexes. Here, we studied molecular signaling that underlies estrogen-induced and activity-dependent potentiation of excitatory synapses in the hippocampus. We found that, despite similar magnitude increases in synaptic strength in males and females, the roles of cAMP-regulated protein kinase, internal calcium stores, and L-type calcium channels differ between the sexes. Therefore, latent sex differences in which the same outcome is achieved through distinct underlying mechanisms in males and females include kinase and calcium signaling involved in synaptic potentiation, demonstrating that sex is an important factor in identification of molecular targets for therapeutic development based on mechanisms of neuromodulation.
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20
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MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias. Proc Natl Acad Sci U S A 2018; 115:E12407-E12416. [PMID: 30530649 DOI: 10.1073/pnas.1816177115] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The genetically heterogeneous spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of nonreceptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degenerative disease. Here we reveal that the SFK suppressor Missing-in-metastasis (MTSS1) is an ataxia locus that links multiple SCAs. MTSS1 loss results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by cell death. Surprisingly, mouse models for SCA1, SCA2, and SCA5 show elevated SFK activity, with SCA1 and SCA2 displaying dramatically reduced MTSS1 protein levels through reduced gene expression and protein translation, respectively. Treatment of each SCA model with a clinically approved Src inhibitor corrects Purkinje neuron basal firing and delays ataxia progression in MTSS1 mutants. Our results identify a common SCA therapeutic target and demonstrate a key role for MTSS1/SFK in Purkinje neuron survival and ataxia progression.
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21
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Sullivan JA, Zhang XL, Sullivan AP, Vose LR, Moghadam AA, Fried VA, Stanton PK. Zinc enhances hippocampal long-term potentiation at CA1 synapses through NR2B containing NMDA receptors. PLoS One 2018; 13:e0205907. [PMID: 30485271 PMCID: PMC6261414 DOI: 10.1371/journal.pone.0205907] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 10/03/2018] [Indexed: 01/16/2023] Open
Abstract
The role of zinc (Zn2+), a modulator of N-methyl-D-aspartate (NMDA) receptors, in regulating long-term synaptic plasticity at hippocampal CA1 synapses is poorly understood. The effects of exogenous application of Zn2+ and of chelation of endogenous Zn2+ were examined on long-term potentiation (LTP) of stimulus-evoked synaptic transmission at Schaffer collateral (SCH) synapses in field CA1 of mouse hippocampal slices using whole-cell patch clamp and field recordings. Low micromolar concentrations of exogenous Zn2+ enhanced the induction of LTP, and this effect required activation of NMDA receptors containing NR2B subunits. Zn2+ elicited a selective increase in NMDA/NR2B fEPSPs, and removal of endogenous Zn2+ with high-affinity Zn2+ chelators robustly reduced the magnitude of stimulus-evoked LTP. Taken together, our data show that Zn2+ at physiological concentrations enhances activation of NMDA receptors containing NR2B subunits, and that this effect enhances the magnitude of LTP.
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Affiliation(s)
- John A. Sullivan
- Cell Biology & Anatomy, New York Medical College, Valhalla, New York, United States of America
- * E-mail:
| | - Xiao-lei Zhang
- Cell Biology & Anatomy, New York Medical College, Valhalla, New York, United States of America
| | - Arthur P. Sullivan
- Psychology & Education, Touro School of Health Sciences, New York, New York, United States of America
| | - Linnea R. Vose
- Cell Biology & Anatomy, New York Medical College, Valhalla, New York, United States of America
| | - Alexander A. Moghadam
- Cell Biology & Anatomy, New York Medical College, Valhalla, New York, United States of America
| | - Victor A. Fried
- Cell Biology & Anatomy, New York Medical College, Valhalla, New York, United States of America
| | - Patric K. Stanton
- Cell Biology & Anatomy, New York Medical College, Valhalla, New York, United States of America
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22
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Memory-Related Synaptic Plasticity Is Sexually Dimorphic in Rodent Hippocampus. J Neurosci 2018; 38:7935-7951. [PMID: 30209204 DOI: 10.1523/jneurosci.0801-18.2018] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 06/22/2018] [Accepted: 07/15/2018] [Indexed: 12/22/2022] Open
Abstract
Men are generally superior to women in remembering spatial relationships, whereas the reverse holds for semantic information, but the neurobiological bases for these differences are not understood. Here we describe striking sexual dimorphism in synaptic mechanisms of memory encoding in hippocampal field CA1, a region critical for spatial learning. Studies of acute hippocampal slices from adult rats and mice show that for excitatory Schaffer-commissural projections, the memory-related long-term potentiation (LTP) effect depends upon endogenous estrogen and membrane estrogen receptor α (ERα) in females but not in males; there was no evident involvement of nuclear ERα in females, or of ERβ or GPER1 (G-protein-coupled estrogen receptor 1) in either sex. Quantitative immunofluorescence showed that stimulation-induced activation of two LTP-related kinases (Src, ERK1/2), and of postsynaptic TrkB, required ERα in females only, and that postsynaptic ERα levels are higher in females than in males. Several downstream signaling events involved in LTP were comparable between the sexes. In contrast to endogenous estrogen effects, infused estradiol facilitated LTP and synaptic signaling in females via both ERα and ERβ. The estrogen dependence of LTP in females was associated with a higher threshold for both inducing potentiation and acquiring spatial information. These results indicate that the observed sexual dimorphism in hippocampal LTP reflects differences in synaptic kinase activation, including both a weaker association with NMDA receptors and a greater ERα-mediated kinase activation in response to locally produced estrogen in females. We propose that male/female differences in mechanisms and threshold for field CA1 LTP contribute to differences in encoding specific types of memories.SIGNIFICANCE STATEMENT There is good evidence for male/female differences in memory-related cognitive function, but the neurobiological basis for this sexual dimorphism is not understood. Here we describe sex differences in synaptic function in a brain area that is critical for learning spatial cues. Our results show that female rodents have higher synaptic levels of estrogen receptor α (ERα) and, in contrast to males, require membrane ERα for the activation of signaling kinases that support long-term potentiation (LTP), a form of synaptic plasticity thought to underlie learning. The additional requirement of estrogen signaling in females resulted in a higher threshold for both LTP and hippocampal field CA1-dependent spatial learning. These results describe a synaptic basis for sexual dimorphism in encoding spatial information.
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23
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Nagappan-Chettiar S, Johnson-Venkatesh EM, Umemori H. Tyrosine phosphorylation of the transmembrane protein SIRPα: Sensing synaptic activity and regulating ectodomain cleavage for synapse maturation. J Biol Chem 2018; 293:12026-12042. [PMID: 29914984 DOI: 10.1074/jbc.ra117.001488] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 06/08/2018] [Indexed: 11/06/2022] Open
Abstract
Synapse maturation is a neural activity-dependent process during brain development, in which active synapses preferentially undergo maturation to establish efficient neural circuits in the brain. Defects in this process are implicated in various neuropsychiatric disorders. We have previously reported that a postsynaptic transmembrane protein, signal regulatory protein-α (SIRPα), plays an important role in activity-dependently directing synapse maturation. In the presence of synaptic activity, the ectodomain of SIRPα is cleaved and released and then acts as a retrograde signal to induce presynaptic maturation. However, how SIRPα detects synaptic activity to promote its ectodomain cleavage and synapse maturation is unknown. Here, we show that activity-dependent tyrosine phosphorylation of SIRPα is critical for SIRPα cleavage and synapse maturation. We found that during synapse maturation and in response to neural activity, SIRPα is highly phosphorylated on its tyrosine residues in the hippocampus, a structure critical for learning and memory. Tyrosine phosphorylation of SIRPα was necessary for SIRPα cleavage and presynaptic maturation, as indicated by the fact that a phosphorylation-deficient SIRPα variant underwent much less cleavage and could not drive presynaptic maturation. However, SIRPα phosphorylation did not affect its synaptic localization. Finally, we show that inhibitors of the Src and JAK kinase family suppress neural activity-dependent SIRPα phosphorylation and cleavage. Together, our results indicate that SIRPα phosphorylation serves as a mechanism for detecting synaptic activity and linking it to the ectodomain cleavage of SIRPα, which in turn drives synapse maturation in an activity-dependent manner.
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Affiliation(s)
- Sivapratha Nagappan-Chettiar
- Department of Neurology, F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts 02115; Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115
| | - Erin M Johnson-Venkatesh
- Department of Neurology, F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts 02115
| | - Hisashi Umemori
- Department of Neurology, F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts 02115; Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115.
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24
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Ding S, Zhuge W, Yang J, Wen F, Xu Z, Wang X, Zhuge Q. Insulin Resistance Disrupts the Interaction Between AKT and the NMDA Receptor and the Inactivation of the CaMKIV/CREB Pathway in Minimal Hepatic Encephalopathy. Toxicol Sci 2017; 159:290-306. [PMID: 28505381 DOI: 10.1093/toxsci/kfx093] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025] Open
Abstract
Hepatic cirrhosis-induced Minimal hepatic encephalopathy (MHE) has been characterized for cognitive dysfunction and central nervous system (CNS) insulin resistance (IR) has been acknowledged to be closely correlated with cognitive impairment while hepatic cirrhosis has been recognized to induce IR. Thus, this study aimed to investigate whether CNS IR occurred in MHE and induced MHE, as well as the underlying mechanism. We found IR in the MHE rats, an especially decreased level of the insulin receptor (InsR), and an increased serine phosphorylation of IRS1 in CNS. PI3K/AKT pathway signaling to the phosphorylation of N-Methyl-d-Aspartate receptors (NMDA receptors, NRs, NR1/NR2B) and downstream activation of the CaMKIV/CREB pathway and final production of neurotrophic factors were triggered by insulin, but impaired in the MHE rats. Additionally, CNS IR, memory impairment, the desensitization of the PI3K/AKT/NMDA receptor (NR)/CaMKIV/CREB pathway and decreased production of BDNF/NT3 in MHE rats were improved by rosiglitazone (RSG). These results suggested that IR, which induces the deficits in the insulin-mediated PI3K/AKT/NR/CaMKIV/CREB/neurotrophin pathway and subsequent memory decline, contributes to the pathogenesis of MHE.
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Affiliation(s)
- Saidan Ding
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disease Research, Department of Surgery Laboratory
| | | | - Jianjing Yang
- Neurosurgery Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Fangfang Wen
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disease Research, Department of Surgery Laboratory
| | - Zhu Xu
- Neurosurgery Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Xuebao Wang
- Analytical and Testing Center, Wenzhou Medical University, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Qichuan Zhuge
- Analytical and Testing Center, Wenzhou Medical University, Wenzhou, Zhejiang 325000, People's Republic of China
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25
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Inhibition of IL-1β Signaling Normalizes NMDA-Dependent Neurotransmission and Reduces Seizure Susceptibility in a Mouse Model of Creutzfeldt-Jakob Disease. J Neurosci 2017; 37:10278-10289. [PMID: 28924012 DOI: 10.1523/jneurosci.1301-17.2017] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 07/31/2017] [Accepted: 08/23/2017] [Indexed: 11/21/2022] Open
Abstract
Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disorder caused by prion protein (PrP) misfolding, clinically recognized by cognitive and motor deficits, electroencephalographic abnormalities, and seizures. Its neurophysiological bases are not known. To assess the potential involvement of NMDA receptor (NMDAR) dysfunction, we analyzed NMDA-dependent synaptic plasticity in hippocampal slices from Tg(CJD) mice, which model a genetic form of CJD. Because PrP depletion may result in functional upregulation of NMDARs, we also analyzed PrP knock-out (KO) mice. Long-term potentiation (LTP) at the Schaffer collateral-commissural synapses in the CA1 area of ∼100-d-old Tg(CJD) mice was comparable to that of wild-type (WT) controls, but there was an inversion of metaplasticity, with increased GluN2B phosphorylation, which is indicative of enhanced NMDAR activation. Similar but less marked changes were seen in PrP KO mice. At ∼300 d of age, the magnitude of LTP increased in Tg(CJD) mice but decreased in PrP KO mice, indicating divergent changes in hippocampal synaptic responsiveness. Tg(CJD) but not PrP KO mice were intrinsically more susceptible than WT controls to focal hippocampal seizures induced by kainic acid. IL-1β-positive astrocytes increased in the Tg(CJD) hippocampus, and blocking IL-1 receptor signaling restored normal synaptic responses and reduced seizure susceptibility. These results indicate that alterations in NMDA-dependent glutamatergic transmission in Tg(CJD) mice do not depend solely on PrP functional loss. Moreover, astrocytic IL-1β plays a role in the enhanced synaptic responsiveness and seizure susceptibility, suggesting that targeting IL-1β signaling may offer a novel symptomatic treatment for CJD.SIGNIFICANCE STATEMENT Dementia and myoclonic jerks develop in individuals with Creutzfeldt-Jakob disease (CJD), an incurable brain disorder caused by alterations in prion protein structure. These individuals are prone to seizures and have high brain levels of the inflammatory cytokine IL-1β. Here we show that blocking IL-1β receptors with anakinra, the human recombinant form of the endogenous IL-1 receptor antagonist used to treat rheumatoid arthritis, normalizes hippocampal neurotransmission and reduces seizure susceptibility in a CJD mouse model. These results link neuroinflammation to defective neurotransmission and the enhanced susceptibility to seizures in CJD and raise the possibility that targeting IL-1β with clinically available drugs may be beneficial for symptomatic treatment of the disease.
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26
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Scanlon DP, Bah A, Krzeminski M, Zhang W, Leduc-Pessah HL, Dong YN, Forman-Kay JD, Salter MW. An evolutionary switch in ND2 enables Src kinase regulation of NMDA receptors. Nat Commun 2017; 8:15220. [PMID: 28508887 PMCID: PMC5440837 DOI: 10.1038/ncomms15220] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 03/10/2017] [Indexed: 12/22/2022] Open
Abstract
The non-receptor tyrosine kinase Src is a key signalling hub for upregulating the function of N-methyl D-aspartate receptors (NMDARs). Src is anchored within the NMDAR complex via NADH dehydrogenase subunit 2 (ND2), a mitochondrially encoded adaptor protein. The interacting regions between Src and ND2 have been broadly identified, but the interaction between ND2 and the NMDAR has remained elusive. Here we generate a homology model of ND2 and dock it onto the NMDAR via the transmembrane domain of GluN1. This interaction is enabled by the evolutionary loss of three helices in bilaterian ND2 proteins compared to their ancestral homologues. We experimentally validate our model and demonstrate that blocking this interaction with an ND2 fragment identified in our experimental studies prevents Src-mediated upregulation of NMDAR currents in neurons. Our findings establish the mode of interaction between an NMDAR accessory protein with one of the core subunits of the receptor. N-methyl D-aspartate receptor (NMDAR) activity is modulated by Src tyrosine kinase via the mitochondrial protein NADH dehydrogenase subunit 2 (ND2). Here the authors show that ND2 interacts with the transmembrane region of NMDAR GluN1 subunit, a process that is crucial for Src regulation of NMDAR activity.
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Affiliation(s)
- David P Scanlon
- Program in Neurosciences &Mental Health, The Hospital for Sick Children, 686 Bay St, Toronto, Ontario, Canada M5G 0A4.,Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8
| | - Alaji Bah
- Program in Molecular Medicine, The Hospital for Sick Children, 686 Bay St, Toronto, Ontario, Canada M5G 0A4.,Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8
| | - Mickaël Krzeminski
- Program in Molecular Medicine, The Hospital for Sick Children, 686 Bay St, Toronto, Ontario, Canada M5G 0A4.,Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8
| | - Wenbo Zhang
- Program in Neurosciences &Mental Health, The Hospital for Sick Children, 686 Bay St, Toronto, Ontario, Canada M5G 0A4.,Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8
| | - Heather L Leduc-Pessah
- Program in Neurosciences &Mental Health, The Hospital for Sick Children, 686 Bay St, Toronto, Ontario, Canada M5G 0A4.,Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8
| | - Yi Na Dong
- Program in Neurosciences &Mental Health, The Hospital for Sick Children, 686 Bay St, Toronto, Ontario, Canada M5G 0A4.,Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8
| | - Julie D Forman-Kay
- Program in Molecular Medicine, The Hospital for Sick Children, 686 Bay St, Toronto, Ontario, Canada M5G 0A4.,Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8
| | - Michael W Salter
- Program in Neurosciences &Mental Health, The Hospital for Sick Children, 686 Bay St, Toronto, Ontario, Canada M5G 0A4.,Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8
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27
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Dopamine promotes NMDA receptor hypofunction in the retina through D 1 receptor-mediated Csk activation, Src inhibition and decrease of GluN2B phosphorylation. Sci Rep 2017; 7:40912. [PMID: 28098256 PMCID: PMC5241882 DOI: 10.1038/srep40912] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 12/12/2016] [Indexed: 11/21/2022] Open
Abstract
Dopamine and glutamate are critical neurotransmitters involved in light-induced synaptic activity in the retina. In brain neurons, dopamine D1 receptors (D1Rs) and the cytosolic protein tyrosine kinase Src can, independently, modulate the behavior of NMDA-type glutamate receptors (NMDARs). Here we studied the interplay between D1Rs, Src and NMDARs in retinal neurons. We reveal that dopamine-mediated D1R stimulation provoked NMDAR hypofunction in retinal neurons by attenuating NMDA-gated currents, by preventing NMDA-elicited calcium mobilization and by decreasing the phosphorylation of NMDAR subunit GluN2B. This dopamine effect was dependent on upregulation of the canonical D1R/adenylyl cyclase/cAMP/PKA pathway, of PKA-induced activation of C-terminal Src kinase (Csk) and of Src inhibition. Accordingly, knocking down Csk or overexpressing a Csk phosphoresistant Src mutant abrogated the dopamine-induced NMDAR hypofunction. Overall, the interplay between dopamine and NMDAR hypofunction, through the D1R/Csk/Src/GluN2B pathway, might impact on light-regulated synaptic activity in retinal neurons.
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28
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Yan X, Zhang B, Lu W, Peng L, Yang Q, Cao W, Lin S, Yu W, Li X, Ke Y, Li S, Yang W, Luo J. Increased Src Family Kinase Activity Disrupts Excitatory Synaptic Transmission and Impairs Remote Fear Memory in Forebrain Shp2-Deficient Mice. Mol Neurobiol 2016; 54:7235-7250. [PMID: 27796759 DOI: 10.1007/s12035-016-0222-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Accepted: 10/13/2016] [Indexed: 11/29/2022]
Abstract
Src homolog domain-containing phosphatase 2 (Shp2) signals a variety of cellular and physiological functions including learning and memory. Dysregulation of ERK signaling is known to be responsible for the cognitive deficits associated with gain-of-function mutated Shp2 mimicking Noonan syndrome. However, here, we report that CaMKIIα-cre induced knockout (CaSKO) of Shp2 in hippocampal pyramidal neurons resulted in increased Src activity, upregulated phosphorylation of N-methyl-D-aspartate receptors (NMDARs) at Y1325 of GluN2A and at Y1472 of GluN2B, disrupted the balance of synaptic transmission, and impaired long-term potentiation and remote contextual fear memory. Administration of PP2, a specific Src family kinase inhibitor, reversed the tyrosine phosphorylation of NMDARs, restored basal synaptic transmission, and rescued the contextual fear memory deficit in CaSKO mice without altering the phospho-ERK level. Taken together, our results reveal a novel role of Shp2 in NMDAR-dependent synaptic function and fear memory via the Src signaling pathway rather than the ERK pathway, and suggest a complicated mechanism for Shp2-associated cognitive deficits.
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Affiliation(s)
- Xunyi Yan
- Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Bin Zhang
- Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Wen Lu
- Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Lin Peng
- Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Qian Yang
- BIO-X Institute, Shanghai Jiaotong University, Shanghai, 200240, China
| | - Wei Cao
- Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Shen Lin
- Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Wenyue Yu
- Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Xiaoming Li
- Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Yuehai Ke
- Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Shengtian Li
- BIO-X Institute, Shanghai Jiaotong University, Shanghai, 200240, China
| | - Wei Yang
- Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
| | - Jianhong Luo
- Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
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29
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Rosenberger AFN, Hilhorst R, Coart E, García Barrado L, Naji F, Rozemuller AJM, van der Flier WM, Scheltens P, Hoozemans JJM, van der Vies SM. Protein Kinase Activity Decreases with Higher Braak Stages of Alzheimer's Disease Pathology. J Alzheimers Dis 2016; 49:927-43. [PMID: 26519433 PMCID: PMC4927853 DOI: 10.3233/jad-150429] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Alzheimer’s disease (AD) is characterized by a long pre-clinical phase (20–30 years), during which significant brain pathology manifests itself. Disease mechanisms associated with pathological hallmarks remain elusive. Most processes associated with AD pathogenesis, such as inflammation, synaptic dysfunction, and hyper-phosphorylation of tau are dependent on protein kinase activity. The objective of this study was to determine the involvement of protein kinases in AD pathogenesis. Protein kinase activity was determined in postmortem hippocampal brain tissue of 60 patients at various stages of AD and 40 non-demented controls (Braak stages 0-VI) using a peptide-based microarray platform. We observed an overall decrease of protein kinase activity that correlated with disease progression. The phosphorylation of 96.7% of the serine/threonine peptides and 37.5% of the tyrosine peptides on the microarray decreased significantly with increased Braak stage (p-value <0.01). Decreased activity was evident at pre-clinical stages of AD pathology (Braak I-II). Increased phosphorylation was not observed for any peptide. STRING analysis in combination with pathway analysis and identification of kinases responsible for peptide phosphorylation showed the interactions between well-known proteins in AD pathology, including the Ephrin-receptor A1 (EphA1), a risk gene for AD, and sarcoma tyrosine kinase (Src), which is involved in memory formation. Additionally, kinases that have not previously been associated with AD were identified, e.g., protein tyrosine kinase 6 (PTK6/BRK), feline sarcoma oncogene kinase (FES), and fyn-associated tyrosine kinase (FRK). The identified protein kinases are new biomarkers and potential drug targets for early (pre-clinical) intervention.
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Affiliation(s)
- Andrea F N Rosenberger
- Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.,Department of Pathology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
| | - Riet Hilhorst
- PamGene International BV, 's-Hertogenbosch, The Netherlands
| | - Elisabeth Coart
- International Drug Development Institute, Louvain-la-Neuve, Belgium
| | | | - Faris Naji
- PamGene International BV, 's-Hertogenbosch, The Netherlands
| | - Annemieke J M Rozemuller
- Department of Pathology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
| | - Wiesje M van der Flier
- Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.,Department of Epidemiology and Biostatistics, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
| | - Philip Scheltens
- Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
| | - Jeroen J M Hoozemans
- Department of Pathology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
| | - Saskia M van der Vies
- Department of Pathology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
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30
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Yamazaki Y, Sumikawa K. Nicotine-induced neuroplasticity counteracts the effect of schizophrenia-linked neuregulin 1 signaling on NMDAR function in the rat hippocampus. Neuropharmacology 2016; 113:386-395. [PMID: 27784625 DOI: 10.1016/j.neuropharm.2016.10.021] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 10/10/2016] [Accepted: 10/21/2016] [Indexed: 12/13/2022]
Abstract
A high rate of heavy tobacco smoking among people with schizophrenia has been suggested to reflect self-medication and amelioration of cognitive dysfunction, a core feature of schizophrenia. NMDAR hypofunction is hypothesized to be a mechanism of cognitive dysfunction, and excessive schizophrenia-linked neuregulin 1 (NRG1) signaling through its receptor ErbB4 can suppress NMDAR function by preventing Src-mediated enhancement of NMDAR responses. Here we investigated whether chronic nicotine exposure in rats by subcutaneous injection of nicotine (0.5-1 mg/kg, twice daily for 10-15 days) counteracts the suppressive effect of NRG1β on NMDAR-mediated responses recorded from CA1 pyramidal cells in acute hippocampal slices. We found that NRG1β, which prevents the enhancement of NMDAR responses by the Src-family-kinase-activating peptide pYEEI in naive rats, failed to block the effect of pYEEI in nicotine-exposed rats. In naive rats, NRG1β acts only on GluN2B-NMDARs by blocking their Src-mediated upregulation. Chronic nicotine exposure causes enhanced GluN2B-NMDAR responses via Src upregulation and recruits Fyn for the enhancement of GluN2A-NMDAR responses. NRG1β has no effect on both enhanced basal GluN2B-NMDAR responses and Fyn-mediated enhancement of GluN2A-NMDAR responses. Src-mediated enhancement of GluN2B-NMDAR responses and Fyn-mediated enhancement of GluN2A-NMDAR responses initiate long-term potentiation (LTP) of AMPAR synaptic responses in naive and nicotine-exposed CA1 pyramidal cells, respectively. These results suggest that NRG1β suppresses LTP by blocking Src-mediated enhancement of GluN2B-NMDAR responses, but has no effect on LTP in nicotine-exposed rats. These effects of chronic nicotine exposure may counteract the negative effect of increased NRG1-ErbB4 signaling on the cellular mechanisms of learning and memory in individuals with schizophrenia, and therefore may motivate heavy smoking.
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Affiliation(s)
- Yoshihiko Yamazaki
- Department of Neurobiology and Behavior, University of California, Irvine, CA 92697-4550, USA; Department of Neurophysiology, Yamagata University School of Medicine, Yamagata 990-9585, Japan
| | - Katumi Sumikawa
- Department of Neurobiology and Behavior, University of California, Irvine, CA 92697-4550, USA.
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31
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Itoh N, Enomoto A, Nagai T, Takahashi M, Yamada K. Molecular mechanism linking BDNF/TrkB signaling with the NMDA receptor in memory: the role of Girdin in the CNS. Rev Neurosci 2016; 27:481-90. [DOI: 10.1515/revneuro-2015-0072] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Accepted: 01/14/2016] [Indexed: 12/21/2022]
Abstract
AbstractIt is well known that synaptic plasticity is the cellular mechanism underlying learning and memory. Activity-dependent synaptic changes in electrical properties and morphology, including synaptogenesis, lead to alterations of synaptic strength, which is associated with long-term potentiation (LTP). Brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling is involved in learning and memory formation by regulating synaptic plasticity. The phosphatidylinositol 3-kinase (PI3-K)/Akt pathway is one of the key signaling cascades downstream BDNF/TrkB and is believed to modulate N-methyl-d-aspartate (NMDA) receptor-mediated synaptic plasticity. However, the molecular mechanism underlying the connection between these two key players in synaptic plasticity remains largely unknown. Girders of actin filament (Girdin), an Akt substrate that directly binds to actin filaments, has been shown to play a role in neuronal migration and neuronal development. Recently, we identified Girdin as a key molecule involved in regulating long-term memory. It was demonstrated that phosphorylation of Girdin by Akt contributed to the maintenance of LTP by linking the BDNF/TrkB signaling pathway with NMDA receptor activity. These findings indicate that Girdin plays a pivotal role in a variety of processes in the CNS. Here, we review recent advances in our understanding about the roles of Girdin in the CNS and focus particularly on neuronal migration and memory.
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Affiliation(s)
| | | | - Taku Nagai
- 1Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8560, Japan
| | - Masahide Takahashi
- 2Department of Pathology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, Aichi 466-8550, Japan
| | - Kiyofumi Yamada
- 1Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8560, Japan
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Matsuoka H, Inoue M. Src mediates endocytosis of TWIK-related acid-sensitive K+ 1 channels in PC12 cells in response to nerve growth factor. Am J Physiol Cell Physiol 2015; 309:C251-63. [DOI: 10.1152/ajpcell.00354.2014] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 06/10/2015] [Indexed: 01/17/2023]
Abstract
TWIK-related acid-sensitive K+ (TASK) channels produce background K+ currents. We elucidated that TASK1 channels in rat adrenal medullary cells and PC12 cells are internalized in a clathrin-dependent manner in response to nerve growth factor (NGF). Here, the molecular mechanism for this internalization in PC12 cells was explored. The combination of enzyme inhibitors with tropomyosin receptor kinase A mutants revealed that the internalization was mediated by both phospholipase C and phosphatidylinositol 3-kinase pathways that converge on protein kinase C with the consequent activation of Src, a nonreceptor tyrosine kinase. The NGF-induced endocytosis of TASK1 channels did not occur in the presence of the Src inhibitor or with the expression of a kinase-dead Src mutant. Additionally, NGF induced a transient colocalization of Src with the TASK1 channel, but not the TASK1 mutant, in which tyrosine at 370 was replaced with phenylalanine. This TASK1 mutant showed no increase in tyrosine phosphorylation and markedly diminished internalization in response to NGF. We concluded that NGF induces endocytosis of TASK1 channels via tyrosine phosphorylation in its carboxyl terminus.
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Affiliation(s)
- Hidetada Matsuoka
- Department of Cell and Systems Physiology, University of Occupational and Environmental Health School of Medicine, Kitakyushu, Japan
| | - Masumi Inoue
- Department of Cell and Systems Physiology, University of Occupational and Environmental Health School of Medicine, Kitakyushu, Japan
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Abstract
Proteases regulate a myriad of cell functions, both in normal and disease states. In addition to protein turnover, they regulate a range of signaling processes, including those mediated by Eph receptors and their ephrin ligands. A variety of proteases is reported to directly cleave Ephs and/or ephrins under different conditions, to promote receptor and/or ligand shedding, and regulate receptor/ligand internalisation and signaling. They also cleave other adhesion proteins in response to Eph-ephrin interactions, to indirectly facilitate Eph-mediated functions. Proteases thus contribute to Eph/ephrin mediated changes in cell-cell and cell-matrix interactions, in cell morphology and in cell migration and invasion, in a manner which appears to be tightly regulated by, and co-ordinated with, Eph signaling. This review summarizes the current literature describing the function and regulation of protease activities during Eph/ephrin-mediated cell signaling.
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Affiliation(s)
- Lakmali Atapattu
- a Department of Biochemistry and Molecular Biology ; Monash University , Victoria ; Australia
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Lu W, Fang W, Li J, Zhang B, Yang Q, Yan X, Peng L, Ai H, Wang JJ, Liu X, Luo J, Yang W. Phosphorylation of Tyrosine 1070 at the GluN2B Subunit Is Regulated by Synaptic Activity and Critical for Surface Expression of N-Methyl-D-aspartate (NMDA) Receptors. J Biol Chem 2015; 290:22945-54. [PMID: 26229100 DOI: 10.1074/jbc.m115.663450] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Indexed: 01/13/2023] Open
Abstract
The number and subunit composition of synaptic N-methyl-d-aspartate receptors (NMDARs) play critical roles in synaptic plasticity, learning, and memory and are implicated in neurological disorders. Tyrosine phosphorylation provides a powerful means of regulating NMDAR function, but the underling mechanism remains elusive. In this study we identified a tyrosine site on the GluN2B subunit, Tyr-1070, which was phosphorylated by a proto-oncogene tyrosine-protein (Fyn) kinase and critical for the surface expression of GluN2B-containing NMDARs. The phosphorylation of GluN2B at Tyr-1070 was required for binding of Fyn kinase to GluN2B, which up-regulated the phosphorylation of GluN2B at Tyr-1472. Moreover, our results revealed that the phosphorylation change of GluN2B at Tyr-1070 accompanied the Tyr-1472 phosphorylation and Fyn associated with GluN2B in synaptic plasticity induced by both chemical and contextual fear learning. Taken together, our findings provide a new mechanism for regulating the surface expression of NMDARs with implications for synaptic plasticity.
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Affiliation(s)
- Wen Lu
- From the Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Weiqing Fang
- From the Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Jian Li
- From the Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China, Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou, Zhejiang 310027, China, and
| | - Bin Zhang
- From the Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Qian Yang
- From the Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Xunyi Yan
- From the Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Lin Peng
- From the Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Heng Ai
- Department of Physiology, Zhejiang Medical College, Hangzhou, Zhejiang 310053, China
| | - Jie-jie Wang
- From the Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Xiao Liu
- From the Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Jianhong Luo
- From the Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China,
| | - Wei Yang
- From the Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China,
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Bravo D, Maturana CJ, Pelissier T, Hernández A, Constandil L. Interactions of pannexin 1 with NMDA and P2X7 receptors in central nervous system pathologies: Possible role on chronic pain. Pharmacol Res 2015. [PMID: 26211949 DOI: 10.1016/j.phrs.2015.07.016] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Pannexin 1 (Panx1) is a glycoprotein that acts as a membrane channel in a wide variety of tissues in mammals. In the central nervous system (CNS) Panx1 is expressed in neurons, astrocytes and microglia, participating in the pathophysiology of some CNS diseases, such as epilepsy, anoxic depolarization after stroke and neuroinflammation. In these conditions Panx1 acts as an important modulator of the neuroinflammatory response, by secreting ATP, by interacting with the P2X7 receptor (P2X7R), and as an amplifier of NMDA receptor (NMDAR) currents, particularly in conditions of pathological neuronal hyperexcitability. Here, we briefly reviewed the current evidences that support the interaction of Panx1 with NMDAR and P2X7R in pathological contexts of the CNS, with special focus in recent data supporting that Panx1 is involved in chronic pain signaling by interacting with NMDAR in neurons and with P2X7R in glia. The participation of Panx1 in chronic pain constitutes a novel topic for research in the field of clinical neurosciences and a potential target for pharmacological interventions in chronic pain.
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Affiliation(s)
- D Bravo
- Laboratory of Neurobiology, Department of Biology, Faculty of Chemistry and Biology, University of Santiago of Chile, Chile; School of Kinesiology, Faculty of Sport, Health and Recreation, University Bernardo O'Higgins, Chile.
| | - C J Maturana
- Departamento de Fisiología, Pontificia Universidad Católica De Chile, Chile
| | - T Pelissier
- Program of Molecular and Clinical Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Chile
| | - A Hernández
- Laboratory of Neurobiology, Department of Biology, Faculty of Chemistry and Biology, University of Santiago of Chile, Chile
| | - L Constandil
- Laboratory of Neurobiology, Department of Biology, Faculty of Chemistry and Biology, University of Santiago of Chile, Chile
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Abstract
The morphology and the connectivity of neuronal structures formed during early development must be actively maintained as the brain matures. Although impaired axon stability is associated with the progression of various neurological diseases, relatively little is known about the factors controlling this process. We identified Brain tumor (Brat), a conserved member of the TRIM-NHL family of proteins, as a new regulator of axon maintenance in Drosophila CNS. Brat function is dispensable for the initial growth of Mushroom Body axons, but is required for the stabilization of axon bundles. We found that Brat represses the translation of src64B, an upstream regulator of a conserved Rho-dependent pathway previously shown to promote axon retraction. Furthermore, brat phenotypes are phenocopied by src64B overexpression, and partially suppressed by reducing the levels of src64B or components of the Rho pathway, suggesting that brat promotes axon maintenance by downregulating the levels of Src64B. Finally, Brat regulates brain connectivity via its NHL domain, but independently of its previously described partners Nanos, Pumilio, and d4EHP. Thus, our results uncover a novel post-transcriptional regulatory mechanism that controls the maintenance of neuronal architecture by tuning the levels of a conserved rho-dependent signaling pathway.
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Trans-synaptic zinc mobilization improves social interaction in two mouse models of autism through NMDAR activation. Nat Commun 2015; 6:7168. [PMID: 25981743 PMCID: PMC4479043 DOI: 10.1038/ncomms8168] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Accepted: 04/14/2015] [Indexed: 12/19/2022] Open
Abstract
Genetic aspects of autism spectrum disorders (ASDs) have recently been extensively explored, but environmental influences that affect ASDs have received considerably less attention. Zinc (Zn) is a nutritional factor implicated in ASDs, but evidence for a strong association and linking mechanism is largely lacking. Here we report that trans-synaptic Zn mobilization rapidly rescues social interaction in two independent mouse models of ASD. In mice lacking Shank2, an excitatory postsynaptic scaffolding protein, postsynaptic Zn elevation induced by clioquinol (a Zn chelator and ionophore) improves social interaction. Postsynaptic Zn is mainly derived from presynaptic pools and activates NMDA receptors (NMDARs) through postsynaptic activation of the tyrosine kinase Src. Clioquinol also improves social interaction in mice haploinsufficient for the transcription factor Tbr1, which accompanies NMDAR activation in the amygdala. These results suggest that trans-synaptic Zn mobilization induced by clioquinol rescues social deficits in mouse models of ASD through postsynaptic Src and NMDAR activation. Zinc is a nutritional factor implicated in autism spectrum disorders (ASDs), but evidence for a strong association and linking mechanism is largely lacking. Here, the authors report that trans-synaptic zinc mobilization rapidly rescues social interaction in two independent mouse models of ASD.
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Disruption of Src Is Associated with Phenotypes Related to Williams-Beuren Syndrome and Altered Cellular Localization of TFII-I. eNeuro 2015; 2:eN-NWR-0016-14. [PMID: 26464974 PMCID: PMC4596087 DOI: 10.1523/eneuro.0016-14.2015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Revised: 03/02/2015] [Accepted: 03/02/2015] [Indexed: 11/21/2022] Open
Abstract
Src is a nonreceptor protein tyrosine kinase that is expressed widely throughout the central nervous system and is involved in diverse biological functions. Mice homozygous for a spontaneous mutation in Src (Src (thl/thl) ) exhibited hypersociability and hyperactivity along with impairments in visuospatial, amygdala-dependent, and motor learning as well as an increased startle response to loud tones. The phenotype of Src (thl/thl) mice showed significant overlap with Williams-Beuren syndrome (WBS), a disorder caused by the deletion of several genes, including General Transcription Factor 2-I (GTF2I). Src phosphorylation regulates the movement of GTF2I protein (TFII-I) between the nucleus, where it is a transcriptional activator, and the cytoplasm, where it regulates trafficking of transient receptor potential cation channel, subfamily C, member 3 (TRPC3) subunits to the plasma membrane. Here, we demonstrate altered cellular localization of both TFII-I and TRPC3 in the Src mutants, suggesting that disruption of Src can phenocopy behavioral phenotypes observed in WBS through its regulation of TFII-I.
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Kumar A, Jaggi AS, Singh N. Pharmacology of Src family kinases and therapeutic implications of their modulators. Fundam Clin Pharmacol 2015; 29:115-30. [PMID: 25545125 DOI: 10.1111/fcp.12097] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Revised: 11/18/2014] [Accepted: 12/02/2014] [Indexed: 12/23/2022]
Abstract
Src family kinases (SFKs), the largest family of nonreceptor tyrosine kinases, include 10 members. Src was the first gene product discovered to have intrinsic protein tyrosine kinase activity. Src is widely expressed in many cell types and can have different locations within a cell; the subcellular location of Src can affect its function. Src can associate with cellular membranes, such as the plasma membrane, the perinuclear membrane, and the endosomal membrane. SFKs actions on mammalian cells are pleiotropic and include effect on cell morphology, adhesion, migration, invasion, proliferation, differentiation, and survival. SFKs at one end have been documented to play some important physiological functions; on the other end, they have been described in the pathophysiology of some disorders. In this review article, an exhaustive attempt has been made to unearth pharmacology of SFKs and therapeutic implications of SFKs modulators.
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Affiliation(s)
- Amit Kumar
- CNS and CVS Research Laboratory, Pharmacology Division, Department of Pharmaceutical Sciences and Drug Research, Faculty of Medicine, Punjabi University, Patiala, 147002, Punjab, India
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Lian X, Wang XT, Wang WT, Yang X, Suo ZW, Hu XD. Peripheral inflammation activated focal adhesion kinase signaling in spinal dorsal horn of mice. J Neurosci Res 2015; 93:873-81. [DOI: 10.1002/jnr.23551] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Revised: 11/18/2014] [Accepted: 12/15/2014] [Indexed: 12/27/2022]
Affiliation(s)
- Xia Lian
- Department of Molecular Pharmacology; School of Pharmacy, Lanzhou University; Lanzhou Gansu People's Republic of China
| | - Xin-Tai Wang
- Department of Molecular Pharmacology; School of Pharmacy, Lanzhou University; Lanzhou Gansu People's Republic of China
| | - Wen-Tao Wang
- Department of Molecular Pharmacology; School of Pharmacy, Lanzhou University; Lanzhou Gansu People's Republic of China
| | - Xian Yang
- Department of Molecular Pharmacology; School of Pharmacy, Lanzhou University; Lanzhou Gansu People's Republic of China
| | - Zhan-Wei Suo
- Department of Molecular Pharmacology; School of Pharmacy, Lanzhou University; Lanzhou Gansu People's Republic of China
| | - Xiao-Dong Hu
- Department of Molecular Pharmacology; School of Pharmacy, Lanzhou University; Lanzhou Gansu People's Republic of China
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42
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Girdin phosphorylation is crucial for synaptic plasticity and memory: a potential role in the interaction of BDNF/TrkB/Akt signaling with NMDA receptor. J Neurosci 2015; 34:14995-5008. [PMID: 25378165 DOI: 10.1523/jneurosci.2228-14.2014] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Synaptic plasticity in hippocampal neurons has been thought to represent a variety of memories. Although accumulating evidence indicates a crucial role of BDNF/TrkB/Akt signaling in the synaptic plasticity of the hippocampus, the mechanism by which Akt, a serine/threonine kinase, controls activity-dependent neuronal plasticity remains unclear. Girdin (also known as APE, GIV, and HkRP1), an actin-binding protein involved both in the remodeling of the actin cytoskeleton and in cell migration, has been identified as a substrate of Akt. Previous studies have demonstrated that deficit of neuronal migration in the hippocampus of Girdin-deficient (Girdin(-/-)) mice is independent on serine phosphorylation of Girdin at S1416 (Girdin S1416) by Akt. In the present study, we focused on the role of Girdin S1416 phosphorylation in BDNF/TrkB/Akt signaling associated with synaptic plasticity. We found that Girdin in the hippocampus was phosphorylated at S1416 in an activity-dependent manner. Phosphorylation-deficient knock-in mice (Girdin(SA/SA) mice), in which S1416 is replaced with alanine, exhibited shrinkage of spines, deficit of hippocampal long-term potentiation, and memory impairment. These phenotypes of Girdin(SA/SA) mice resembled those of Girdin(+/-) mice, which have 50% loss of Girdin expression. Furthermore, Girdin interacted with Src kinase and NR2B subunit of NMDA receptor, leading to phosphorylation of the NR2B subunit and NMDA receptor activation. Our findings suggest that Girdin has two different functions in the hippocampus: Akt-independent neuronal migration and Akt-dependent NR2B phosphorylation through the interaction with Src, which is associated with synaptic plasticity in the hippocampus underlying memory formation.
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Doré K, Labrecque S, Tardif C, De Koninck P. FRET-FLIM investigation of PSD95-NMDA receptor interaction in dendritic spines; control by calpain, CaMKII and Src family kinase. PLoS One 2014; 9:e112170. [PMID: 25393018 PMCID: PMC4230936 DOI: 10.1371/journal.pone.0112170] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Accepted: 10/13/2014] [Indexed: 11/18/2022] Open
Abstract
Little is known about the changes in protein interactions inside synapses during synaptic remodeling, as their live monitoring in spines has been limited. We used a FRET-FLIM approach in developing cultured rat hippocampal neurons expressing fluorescently tagged NMDA receptor (NMDAR) and PSD95, two essential proteins in synaptic plasticity, to examine the regulation of their interaction. NMDAR stimulation caused a transient decrease in FRET between the NMDAR and PSD95 in spines of young and mature neurons. The activity of both CaMKII and calpain were essential for this effect in both developmental stages. Meanwhile, inhibition of Src family kinase (SFK) had opposing impacts on this decrease in FRET in young versus mature neurons. Our data suggest concerted roles for CaMKII, SFK and calpain activity in regulating activity-dependent separation of PSD95 from GluN2A or GluN2B. Finally, we found that calpain inhibition reduced spine growth that was caused by NMDAR activity, supporting the hypothesis that PSD95-NMDAR separation is implicated in synaptic remodeling.
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Affiliation(s)
- Kim Doré
- Institut Universitaire en Santé Mentale de Québec, Université Laval, Québec, QC, Canada
| | - Simon Labrecque
- Institut Universitaire en Santé Mentale de Québec, Université Laval, Québec, QC, Canada
| | - Christian Tardif
- Institut Universitaire en Santé Mentale de Québec, Université Laval, Québec, QC, Canada
| | - Paul De Koninck
- Institut Universitaire en Santé Mentale de Québec, Université Laval, Québec, QC, Canada
- Département de Biochimie, Microbiologie et Bio-informatique, Université Laval, Québec, QC, Canada
- * E-mail:
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Liu Y, Yang X, Suo Z, Xu Y, Hu X. Fyn kinase-regulated NMDA receptor- and AMPA receptor-dependent pain sensitization in spinal dorsal horn of mice. Eur J Pain 2014; 18:1120-8. [DOI: 10.1002/j.1532-2149.2014.00455.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/10/2013] [Indexed: 11/05/2022]
Affiliation(s)
- Y.N. Liu
- Department of Molecular Pharmacology; School of Pharmacy; Lanzhou University; Gansu China
- College of Chemistry and Chemical Engineering; Lanzhou University; Gansu China
| | - X. Yang
- Department of Molecular Pharmacology; School of Pharmacy; Lanzhou University; Gansu China
| | - Z.W. Suo
- Department of Molecular Pharmacology; School of Pharmacy; Lanzhou University; Gansu China
| | - Y.M. Xu
- Department of Molecular Pharmacology; School of Pharmacy; Lanzhou University; Gansu China
| | - X.D. Hu
- Department of Molecular Pharmacology; School of Pharmacy; Lanzhou University; Gansu China
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45
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Moriguchi S, Tanaka T, Narahashi T, Fukunaga K. Novel nootropic drug sunifiram enhances hippocampal synaptic efficacy via glycine-binding site ofN-methyl-D-aspartate receptor. Hippocampus 2013; 23:942-51. [DOI: 10.1002/hipo.22150] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/21/2013] [Indexed: 12/25/2022]
Affiliation(s)
- Shigeki Moriguchi
- Department of Pharmacology; Graduate School of Pharmaceutical Sciences, Tohoku University; Sendai Japan
- Department of Molecular Pharmacology and Biological Chemistry; Northwestern University Feinberg School of Medicine; Chicago Illinois
| | - Tomoya Tanaka
- Department of Pharmacology; Graduate School of Pharmaceutical Sciences, Tohoku University; Sendai Japan
| | - Toshio Narahashi
- Department of Molecular Pharmacology and Biological Chemistry; Northwestern University Feinberg School of Medicine; Chicago Illinois
| | - Kohji Fukunaga
- Department of Pharmacology; Graduate School of Pharmaceutical Sciences, Tohoku University; Sendai Japan
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Tyrosine phosphorylation regulates the endocytosis and surface expression of GluN3A-containing NMDA receptors. J Neurosci 2013; 33:4151-64. [PMID: 23447623 DOI: 10.1523/jneurosci.2721-12.2013] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Selective control of receptor trafficking provides a mechanism for remodeling the receptor composition of excitatory synapses, and thus supports synaptic transmission, plasticity, and development. GluN3A (formerly NR3A) is a nonconventional member of the NMDA receptor (NMDAR) subunit family, which endows NMDAR channels with low calcium permeability and reduced magnesium sensitivity compared with NMDARs comprising only GluN1 and GluN2 subunits. Because of these special properties, GluN3A subunits act as a molecular brake to limit the plasticity and maturation of excitatory synapses, pointing toward GluN3A removal as a critical step in the development of neuronal circuitry. However, the molecular signals mediating GluN3A endocytic removal remain unclear. Here we define a novel endocytic motif (YWL), which is located within the cytoplasmic C-terminal tail of GluN3A and mediates its binding to the clathrin adaptor AP2. Alanine mutations within the GluN3A endocytic motif inhibited clathrin-dependent internalization and led to accumulation of GluN3A-containing NMDARs at the cell surface, whereas mimicking phosphorylation of the tyrosine residue promoted internalization and reduced cell-surface expression as shown by immunocytochemical and electrophysiological approaches in recombinant systems and rat neurons in primary culture. We further demonstrate that the tyrosine residue is phosphorylated by Src family kinases, and that Src-activation limits surface GluN3A expression in neurons. Together, our results identify a new molecular signal for GluN3A internalization that couples the functional surface expression of GluN3A-containing receptors to the phosphorylation state of GluN3A subunits, and provides a molecular framework for the regulation of NMDAR subunit composition with implications for synaptic plasticity and neurodevelopment.
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Snyder MA, Gao WJ. NMDA hypofunction as a convergence point for progression and symptoms of schizophrenia. Front Cell Neurosci 2013; 7:31. [PMID: 23543703 PMCID: PMC3608949 DOI: 10.3389/fncel.2013.00031] [Citation(s) in RCA: 171] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Accepted: 03/11/2013] [Indexed: 01/05/2023] Open
Abstract
Schizophrenia is a disabling mental illness that is now recognized as a neurodevelopmental disorder. It is likely that genetic risk factors interact with environmental perturbations to affect normal brain development and that this altered trajectory results in a combination of positive, negative, and cognitive symptoms. Although the exact pathophysiology of schizophrenia is unknown, the N-methyl-D-aspartate receptor (NMDAR), a major glutamate receptor subtype, has received great attention. Proper expression and regulation of NMDARs in the brain is critical for learning and memory processes as well as cortical plasticity and maturation. Evidence from both animal models and human studies implicates a dysfunction of NMDARs both in disease progression and symptoms of schizophrenia. Furthermore, mutations in many of the known genetic risk factors for schizophrenia suggest that NMDAR hypofunction is a convergence point for schizophrenia. In this review, we discuss how disrupted NMDAR function leads to altered neurodevelopment that may contribute to the progression and development of symptoms for schizophrenia, particularly cognitive deficits. We review the shared signaling pathways among the schizophrenia susceptibility genes DISC1, neuregulin1, and dysbindin, focusing on the AKT/GSK3β pathway, and how their mutations and interactions can lead to NMDAR dysfunction during development. Additionally, we explore what open questions remain and suggest where schizophrenia research needs to move in order to provide mechanistic insight into the cause of NMDAR dysfunction, as well as generate possible new avenues for therapeutic intervention.
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Affiliation(s)
- Melissa A Snyder
- Department of Neurobiology and Anatomy, Drexel University College of Medicine Philadelphia, PA, USA
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PKCλ is critical in AMPA receptor phosphorylation and synaptic incorporation during LTP. EMBO J 2013; 32:1365-80. [PMID: 23511975 DOI: 10.1038/emboj.2013.60] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2012] [Accepted: 02/13/2013] [Indexed: 01/26/2023] Open
Abstract
Direct phosphorylation of GluA1 by PKC controls α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptor (AMPAR) incorporation into active synapses during long-term potentiation (LTP). Numerous signalling molecules that involved in AMPAR incorporation have been identified, but the specific PKC isoform(s) participating in GluA1 phosphorylation and the molecule triggering PKC activation remain largely unknown. Here, we report that the atypical isoform of PKC, PKCλ, is a critical molecule that acts downstream of phosphatidylinositol 3-kinase (PI3K) and is essential for LTP expression. PKCλ activation is required for both GluA1 phosphorylation and increased surface expression of AMPARs during LTP. Moreover, p62 interacts with both PKCλ and GluA1 during LTP and may serve as a scaffolding protein to place PKCλ in close proximity to facilitate GluA1 phosphorylation by PKCλ. Thus, we conclude that PKCλ is the critical signalling molecule responsible for GluA1-containing AMPAR phosphorylation and synaptic incorporation at activated synapses during LTP expression.
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MacDonald JF, Belrose JC, Xie YF, Jackson MF. Nonselective cation channels and links to hippocampal ischemia, aging, and dementia. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2013; 961:433-47. [PMID: 23224901 DOI: 10.1007/978-1-4614-4756-6_37] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Stroke is a very strong risk factor for dementia. Furthermore, ischemic stroke and Alzheimer's disease (AD) share a number of overlapping mechanisms of neuron loss and dysfunction, including those induced by the inappropriate activation of N-methyl-D-aspartate receptors (NMDARs). These receptors form a major subtype of excitatory glutamate receptor. They are nonselective cation channels with appreciable Ca(2+) permeability, and their overactivation leads to neurotoxicity in the cortex and hippocampus. NMDARs have therefore been therapeutic targets in both conditions, but they have failed in the treatment of stroke, and there is limited rationale for using them in treating AD. In this chapter, we discuss current understanding of subtypes of NMDARs and their potential roles in -ischemic stroke and AD. We also discuss the properties of several other nonselective cation channels, transient receptor potential melastatin 2 and 7 channels, and their implications in linking these conditions.
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Affiliation(s)
- John F MacDonald
- Department of Anatomy and Cell Biology, University of Western Ontario, London, ON, Canada.
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Kim EJ, Monje FJ, Li L, Höger H, Pollak DD, Lubec G. Alzheimer's disease risk factor lymphocyte-specific protein tyrosine kinase regulates long-term synaptic strengthening, spatial learning and memory. Cell Mol Life Sci 2013; 70:743-59. [PMID: 23007847 PMCID: PMC11113176 DOI: 10.1007/s00018-012-1168-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2012] [Revised: 08/27/2012] [Accepted: 09/11/2012] [Indexed: 12/21/2022]
Abstract
The lymphocyte-specific protein tyrosine kinase (Lck), which belongs to the Src kinase-family, is expressed in neurons of the hippocampus, a structure critical for learning and memory. Recent evidence demonstrated a significant downregulation of Lck in Alzheimer's disease. Lck has additionally been proposed to be a risk factor for Alzheimer's disease, thus suggesting the involvement of Lck in memory function. The neuronal role of Lck, however, and its involvement in learning and memory remain largely unexplored. Here, in vitro electrophysiology, confocal microscopy, and molecular, pharmacological, genetic and biochemical techniques were combined with in vivo behavioral approaches to examine the role of Lck in the mouse hippocampus. Specific pharmacological inhibition and genetic silencing indicated the involvement of Lck in the regulation of neuritic outgrowth. In the functional pre-established synaptic networks that were examined electrophysiologically, specific Lck-inhibition also selectively impaired the long-term hippocampal synaptic plasticity without affecting spontaneous excitatory synaptic transmission or short-term synaptic potentiation. The selective inhibition of Lck also significantly altered hippocampus-dependent spatial learning and memory in vivo. These data provide the basis for the functional characterization of brain Lck, describing the importance of Lck as a critical regulator of both neuronal morphology and in vivo long-term memory.
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Affiliation(s)
- Eun-Jung Kim
- Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, I, 1090 Vienna, Austria
- Department of Pediatrics, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
| | - Francisco J. Monje
- Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, I, 1090 Vienna, Austria
| | - Lin Li
- Department of Pediatrics, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
| | - Harald Höger
- Core Unit of Biomedical Research, Division of Laboratory Animal Science and Genetics, Medical University of Vienna, Brauhausgasse 34, 2325 Himberg, Austria
| | - Daniela D. Pollak
- Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, I, 1090 Vienna, Austria
| | - Gert Lubec
- Department of Pediatrics, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
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