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1
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Vitureira N, Rafael A, Abudara V. P2X7 receptors and pannexin1 hemichannels shape presynaptic transmission. Purinergic Signal 2024; 20:223-236. [PMID: 37713157 PMCID: PMC11189373 DOI: 10.1007/s11302-023-09965-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 09/06/2023] [Indexed: 09/16/2023] Open
Abstract
Over the last decades, since the discovery of ATP as a transmitter, accumulating evidence has been reported about the role of this nucleotide and purinergic receptors, in particular P2X7 receptors, in the modulation of synaptic strength and plasticity. Purinergic signaling has emerged as a crucial player in orchestrating the molecular interaction between the components of the tripartite synapse, and much progress has been made in how this neuron-glia interaction impacts neuronal physiology under basal and pathological conditions. On the other hand, pannexin1 hemichannels, which are functionally linked to P2X7 receptors, have appeared more recently as important modulators of excitatory synaptic function and plasticity under diverse contexts. In this review, we will discuss the contribution of ATP, P2X7 receptors, and pannexin hemichannels to the modulation of presynaptic strength and its impact on motor function, sensory processing, synaptic plasticity, and neuroglial communication, with special focus on the P2X7 receptor/pannexin hemichannel interplay. We also address major hypotheses about the role of this interaction in physiological and pathological circumstances.
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Affiliation(s)
- Nathalia Vitureira
- Departamento de Fisiología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
| | - Alberto Rafael
- Departamento de Fisiología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Verónica Abudara
- Departamento de Fisiología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
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2
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Luo Y, Zheng S, Xiao W, Zhang H, Li Y. Pannexins in the musculoskeletal system: new targets for development and disease progression. Bone Res 2024; 12:26. [PMID: 38705887 PMCID: PMC11070431 DOI: 10.1038/s41413-024-00334-8] [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: 12/08/2023] [Revised: 03/04/2024] [Accepted: 04/01/2024] [Indexed: 05/07/2024] Open
Abstract
During cell differentiation, growth, and development, cells can respond to extracellular stimuli through communication channels. Pannexin (Panx) family and connexin (Cx) family are two important types of channel-forming proteins. Panx family contains three members (Panx1-3) and is expressed widely in bone, cartilage and muscle. Although there is no sequence homology between Panx family and Cx family, they exhibit similar configurations and functions. Similar to Cxs, the key roles of Panxs in the maintenance of physiological functions of the musculoskeletal system and disease progression were gradually revealed later. Here, we seek to elucidate the structure of Panxs and their roles in regulating processes such as osteogenesis, chondrogenesis, and muscle growth. We also focus on the comparison between Cx and Panx. As a new key target, Panxs expression imbalance and dysfunction in muscle and the therapeutic potentials of Panxs in joint diseases are also discussed.
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Affiliation(s)
- Yan Luo
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Department of Clinical Medicine, Xiangya Medicine School, Central South University, Changsha, Hunan, 410008, China
| | - Shengyuan Zheng
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Department of Clinical Medicine, Xiangya Medicine School, Central South University, Changsha, Hunan, 410008, China
| | - Wenfeng Xiao
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Hang Zhang
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
| | - Yusheng Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
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3
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Shao M, Yu H, Santhakumar V, Yu J. Antiepileptogenic and neuroprotective effect of mefloquine after experimental status epilepticus. Epilepsy Res 2023; 198:107257. [PMID: 37989006 DOI: 10.1016/j.eplepsyres.2023.107257] [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: 08/04/2023] [Revised: 10/30/2023] [Accepted: 11/06/2023] [Indexed: 11/23/2023]
Abstract
Acquired temporal lobe epilepsy (TLE) characterized by spontaneous recurrent seizures (SRS) and hippocampal inhibitory neuron dysfunction is often refractory to current therapies. Gap junctional or electrical coupling between inhibitory neurons has been proposed to facilitate network synchrony and intercellular molecular exchange suggesting a role in both seizures and neurodegeneration. While gap junction blockers can limit acute seizures, whether blocking neuronal gap junctions can modify development of chronic epilepsy has not been examined. This study examined whether mefloquine, a selective blocker of Connexin 36 gap junctions which are well characterized in inhibitory neurons, can limit epileptogenesis and related cellular and behavioral pathology in a model of acquired TLE. A single, systemic dose of mefloquine administered early after pilocarpine-induced status epilepticus (SE) in rat reduced both development of SRS and behavioral co-morbidities. Immunostaining for interneuron subtypes identified that mefloquine treatment likely reduced delayed inhibitory neuronal loss after SE. Uniquely, parvalbumin expressing neurons in the hippocampal dentate gyrus appeared relatively resistant to early cell loss after SE. Functionally, whole cell patch clamp recordings revealed that mefloquine treatment preserved inhibitory synaptic drive to projection neurons one week and one month after SE. These results demonstrate that mefloquine, a drug already approved for malaria prophylaxis, is potentially antiepileptogenic and can protect against progressive interneuron loss and behavioral co-morbidities of epilepsy.
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Affiliation(s)
- Mingting Shao
- Department of Neurosurgery, the First Affiliated Hospital of Bengbu Medical College, Bengbu, China; Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Hang Yu
- Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Vijayalakshmi Santhakumar
- Department of Molecular, Cell and Systems Biology, University of California Riverside, Riverside, CA 92521, USA
| | - Jiandong Yu
- Department of Neurosurgery, the First Affiliated Hospital of Bengbu Medical College, Bengbu, China.
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4
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Moroz LL, Romanova DY. Alternative neural systems: What is a neuron? (Ctenophores, sponges and placozoans). Front Cell Dev Biol 2022; 10:1071961. [PMID: 36619868 PMCID: PMC9816575 DOI: 10.3389/fcell.2022.1071961] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 12/13/2022] [Indexed: 12/24/2022] Open
Abstract
How to make a neuron, a synapse, and a neural circuit? Is there only one 'design' for a neural architecture with a universally shared genomic blueprint across species? The brief answer is "No." Four early divergent lineages from the nerveless common ancestor of all animals independently evolved distinct neuroid-type integrative systems. One of these is a subset of neural nets in comb jellies with unique synapses; the second lineage is the well-known Cnidaria + Bilateria; the two others are non-synaptic neuroid systems in sponges and placozoans. By integrating scRNA-seq and microscopy data, we revise the definition of neurons as synaptically-coupled polarized and highly heterogenous secretory cells at the top of behavioral hierarchies with learning capabilities. This physiological (not phylogenetic) definition separates 'true' neurons from non-synaptically and gap junction-coupled integrative systems executing more stereotyped behaviors. Growing evidence supports the hypothesis of multiple origins of neurons and synapses. Thus, many non-bilaterian and bilaterian neuronal classes, circuits or systems are considered functional rather than genetic categories, composed of non-homologous cell types. In summary, little-explored examples of convergent neuronal evolution in representatives of early branching metazoans provide conceptually novel microanatomical and physiological architectures of behavioral controls in animals with prospects of neuro-engineering and synthetic biology.
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Affiliation(s)
- Leonid L. Moroz
- Departments of Neuroscience and McKnight Brain Institute, University of Florida, Gainesville, FL, United States
- Whitney Laboratory for Marine Bioscience, University of Florida, St. Augustine, FL, United States
| | - Daria Y. Romanova
- Institute of Higher Nervous Activity and Neurophysiology of RAS, 5A Butlerova, Moscow, Russia
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5
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McDouall A, Zhou KQ, Bennet L, Green CR, Gunn AJ, Davidson JO. Connexins, Pannexins and Gap Junctions in Perinatal Brain Injury. Biomedicines 2022; 10:1445. [PMID: 35740466 PMCID: PMC9220888 DOI: 10.3390/biomedicines10061445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/15/2022] [Accepted: 06/15/2022] [Indexed: 11/18/2022] Open
Abstract
Perinatal brain injury secondary to hypoxia-ischemia and/or infection/inflammation remains a major cause of disability. Therapeutic hypothermia significantly improves outcomes, but in randomized controlled trials nearly half of infants still died or survived with disability, showing that additional interventions are needed. There is growing evidence that brain injury spreads over time from injured to previously uninjured regions of the brain. At least in part, this spread is related to opening of connexin hemichannels and pannexin channels, both of which are large conductance membrane channels found in many brain cells. Opening of these membrane channels releases adenosine triphosphate (ATP), and other neuroactive molecules, into the extracellular space. ATP has an important role in normal signaling, but pathologically can trigger the assembly of the multi-protein inflammasome complex. The inflammasome complex promotes activation of inflammatory caspases, and release of inflammatory cytokines. Overall, the connexin hemichannel appears to play a primary role in propagation of injury and chronic disease, and connexin hemichannel blockade has been shown to be neuroprotective in multiple animal models. Thus, there is potential for some blockers of connexin or pannexin channels to be developed into targeted interventions that could be used in conjunction with or separate to therapeutic hypothermia.
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Affiliation(s)
- Alice McDouall
- U1 Department of Physiology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand; (A.M.); (K.Q.Z.); (L.B.); (A.J.G.)
| | - Kelly Q. Zhou
- U1 Department of Physiology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand; (A.M.); (K.Q.Z.); (L.B.); (A.J.G.)
| | - Laura Bennet
- U1 Department of Physiology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand; (A.M.); (K.Q.Z.); (L.B.); (A.J.G.)
| | - Colin R. Green
- Department of Ophthalmology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand;
| | - Alistair J. Gunn
- U1 Department of Physiology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand; (A.M.); (K.Q.Z.); (L.B.); (A.J.G.)
| | - Joanne O. Davidson
- U1 Department of Physiology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand; (A.M.); (K.Q.Z.); (L.B.); (A.J.G.)
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6
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Suarez-Berumen K, Collins-Hooper H, Gromova A, Meech R, Sacco A, Dash PR, Mitchell R, Shestopalov VI, Woolley TE, Vaiyapuri S, Patel K, Makarenkova HP. Pannexin 1 Regulates Skeletal Muscle Regeneration by Promoting Bleb-Based Myoblast Migration and Fusion Through a Novel Lipid Based Signaling Mechanism. Front Cell Dev Biol 2021; 9:736813. [PMID: 34676213 PMCID: PMC8523994 DOI: 10.3389/fcell.2021.736813] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 09/13/2021] [Indexed: 12/12/2022] Open
Abstract
Adult skeletal muscle has robust regenerative capabilities due to the presence of a resident stem cell population called satellite cells. Muscle injury leads to these normally quiescent cells becoming molecularly and metabolically activated and embarking on a program of proliferation, migration, differentiation, and fusion culminating in the repair of damaged tissue. These processes are highly coordinated by paracrine signaling events that drive cytoskeletal rearrangement and cell-cell communication. Pannexins are a family of transmembrane channel proteins that mediate paracrine signaling by ATP release. It is known that Pannexin1 (Panx1) is expressed in skeletal muscle, however, the role of Panx1 during skeletal muscle development and regeneration remains poorly understood. Here we show that Panx1 is expressed on the surface of myoblasts and its expression is rapidly increased upon induction of differentiation and that Panx1-/- mice exhibit impaired muscle regeneration after injury. Panx1-/- myoblasts activate the myogenic differentiation program normally, but display marked deficits in migration and fusion. Mechanistically, we show that Panx1 activates P2 class purinergic receptors, which in turn mediate a lipid signaling cascade in myoblasts. This signaling induces bleb-driven amoeboid movement that in turn supports myoblast migration and fusion. Finally, we show that Panx1 is involved in the regulation of cell-matrix interaction through the induction of ADAMTS (Disintegrin-like and Metalloprotease domain with Thrombospondin-type 5) proteins that help remodel the extracellular matrix. These studies reveal a novel role for lipid-based signaling pathways activated by Panx1 in the coordination of myoblast activities essential for skeletal muscle regeneration.
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Affiliation(s)
- Katia Suarez-Berumen
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, United States.,West Anaheim Medical Center, Anaheim, CA, United States
| | | | - Anastasia Gromova
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, United States.,Development, Aging and Regeneration Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
| | - Robyn Meech
- Department of Clinical Pharmacology, Flinders University, Adelaide, SA, Australia
| | - Alessandra Sacco
- Development, Aging and Regeneration Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
| | - Phil R Dash
- School of Biological Sciences, University of Reading, Reading, United Kingdom
| | - Robert Mitchell
- School of Biological Sciences, University of Reading, Reading, United Kingdom
| | - Valery I Shestopalov
- Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL, United States.,Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia
| | - Thomas E Woolley
- Mathematical Institute, University of Oxford, Oxford, United Kingdom
| | | | - Ketan Patel
- School of Biological Sciences, University of Reading, Reading, United Kingdom
| | - Helen P Makarenkova
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, United States
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7
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Syrjanen J, Michalski K, Kawate T, Furukawa H. On the molecular nature of large-pore channels. J Mol Biol 2021; 433:166994. [PMID: 33865869 PMCID: PMC8409005 DOI: 10.1016/j.jmb.2021.166994] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 04/08/2021] [Accepted: 04/08/2021] [Indexed: 12/25/2022]
Abstract
Membrane transport is a fundamental means to control basic cellular processes such as apoptosis, inflammation, and neurodegeneration and is mediated by a number of transporters, pumps, and channels. Accumulating evidence over the last half century has shown that a type of so-called "large-pore channel" exists in various tissues and organs in gap-junctional and non-gap-junctional forms in order to flow not only ions but also metabolites such as ATP. They are formed by a number of protein families with little or no evolutionary linkages including connexin, innexin, pannexin, leucine-rich repeat-containing 8 (LRRC8), and calcium homeostasis modulator (CALHM). This review summarizes the history and concept of large-pore channels starting from connexin gap junction channels to the more recent developments in innexin, pannexin, LRRC8, and CALHM. We describe structural and functional features of large-pore channels that are crucial for their diverse functions on the basis of available structures.
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Affiliation(s)
- Johanna Syrjanen
- W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Kevin Michalski
- W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Toshimitsu Kawate
- Department of Molecular Medicine, Fields of Biochemistry, Molecular, and Cell Biology (BMCB), and Biophysics, Cornell University, Ithaca, NY 14853, USA
| | - Hiro Furukawa
- W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
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8
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Nemirovskaya TL. ATP-Dependent Pathways of Regulation of Skeletal Muscle Signaling and Their Interaction with Gene Expression under Unloading: The Role of “Slow” Calcium. Biophysics (Nagoya-shi) 2021. [DOI: 10.1134/s0006350921040163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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9
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Battulin N, Kovalzon VM, Korablev A, Serova I, Kiryukhina OO, Pechkova MG, Bogotskoy KA, Tarasova OS, Panchin Y. Pannexin 1 Transgenic Mice: Human Diseases and Sleep-Wake Function Revision. Int J Mol Sci 2021; 22:ijms22105269. [PMID: 34067798 PMCID: PMC8155943 DOI: 10.3390/ijms22105269] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/13/2021] [Accepted: 05/14/2021] [Indexed: 12/26/2022] Open
Abstract
In humans and other vertebrates pannexin protein family was discovered by homology to invertebrate gap junction proteins. Several biological functions were attributed to three vertebrate pannexins members. Six clinically significant independent variants of the PANX1 gene lead to human infertility and oocyte development defects, and the Arg217His variant was associated with pronounced symptoms of primary ovarian failure, severe intellectual disability, sensorineural hearing loss, and kyphosis. At the same time, only mild phenotypes were observed in Panx1 knockout mice. In addition, a passenger mutation was identified in a popular line of Panx1 knockout mice, questioning even those effects. Using CRISPR/Cas9, we created a new line of Panx1 knockout mice and a new line of mice with the clinically significant Panx1 substitution (Arg217His). In both cases, we observed no significant changes in mouse size, weight, or fertility. In addition, we attempted to reproduce a previous study on sleep/wake and locomotor activity functions in Panx1 knockout mice and found that previously reported effects were probably not caused by the Panx1 knockout itself. We consider that the pathological role of Arg217His substitution in Panx1, and some Panx1 functions in general calls for a re-evaluation.
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Affiliation(s)
- Nariman Battulin
- Laboratory of Developmental Genetics, Institute of Cytology and Genetics SB RAS, 630090 Novosibirsk, Russia; (A.K.); (I.S.)
- Correspondence:
| | - Vladimir M. Kovalzon
- Laboratory of Mammal Behavior and Behavioral Ecology, Severtsov Institute Ecology and Evolution, Russian Academy of Sciences, 119071 Moscow, Russia;
- Laboratory for the Study of Information Processes at the Cellular and Molecular Levels, Institute for Information Transmission Problems, Russian Academy of Sciences, 119333 Moscow, Russia; (O.O.K.); (Y.P.)
| | - Alexey Korablev
- Laboratory of Developmental Genetics, Institute of Cytology and Genetics SB RAS, 630090 Novosibirsk, Russia; (A.K.); (I.S.)
| | - Irina Serova
- Laboratory of Developmental Genetics, Institute of Cytology and Genetics SB RAS, 630090 Novosibirsk, Russia; (A.K.); (I.S.)
| | - Oxana O. Kiryukhina
- Laboratory for the Study of Information Processes at the Cellular and Molecular Levels, Institute for Information Transmission Problems, Russian Academy of Sciences, 119333 Moscow, Russia; (O.O.K.); (Y.P.)
- Department of Human and Animal Physiology, Faculty of Biology, M.V. Lomonosov Moscow State University, 119234 Moscow, Russia; (M.G.P.); (K.A.B.); (O.S.T.)
| | - Marta G. Pechkova
- Department of Human and Animal Physiology, Faculty of Biology, M.V. Lomonosov Moscow State University, 119234 Moscow, Russia; (M.G.P.); (K.A.B.); (O.S.T.)
| | - Kirill A. Bogotskoy
- Department of Human and Animal Physiology, Faculty of Biology, M.V. Lomonosov Moscow State University, 119234 Moscow, Russia; (M.G.P.); (K.A.B.); (O.S.T.)
| | - Olga S. Tarasova
- Department of Human and Animal Physiology, Faculty of Biology, M.V. Lomonosov Moscow State University, 119234 Moscow, Russia; (M.G.P.); (K.A.B.); (O.S.T.)
| | - Yuri Panchin
- Laboratory for the Study of Information Processes at the Cellular and Molecular Levels, Institute for Information Transmission Problems, Russian Academy of Sciences, 119333 Moscow, Russia; (O.O.K.); (Y.P.)
- Department of Mathematical Methods in Biology, Belozersky Institute, M.V. Lomonosov Moscow State University, 119234 Moscow, Russia
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10
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Identification and classification of innexin gene transcripts in the central nervous system of the terrestrial slug Limax valentianus. PLoS One 2021; 16:e0244902. [PMID: 33857131 PMCID: PMC8049302 DOI: 10.1371/journal.pone.0244902] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 03/09/2021] [Indexed: 12/20/2022] Open
Abstract
Intercellular gap junction channels and single-membrane channels have been reported to regulate electrical synapse and the brain function. Innexin is known as a gap junction-related protein in invertebrates and is involved in the formation of intercellular gap junction channels and single-cell membrane channels. Multiple isoforms of innexin protein in each species enable the precise regulation of channel function. In molluscan species, sequence information of innexins is still limited and the sequences of multiple innexin isoforms have not been classified. This study examined the innexin transcripts expressed in the central nervous system of the terrestrial slug Limax valentianus and identified 16 transcripts of 12 innexin isoforms, including the splicing variants. We performed phylogenetic analysis and classified the isoforms with other molluscan innexin sequences. Next, the phosphorylation, N-glycosylation, and S-nitrosylation sites were predicted to characterize the innexin isoforms. Further, we identified 16 circular RNA sequences of nine innexin isoforms in the central nervous system of Limax. The identification and classification of molluscan innexin isoforms provided novel insights for understanding the regulatory mechanism of innexin in this phylum.
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11
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Moroz LL, Romanova DY, Kohn AB. Neural versus alternative integrative systems: molecular insights into origins of neurotransmitters. Philos Trans R Soc Lond B Biol Sci 2021; 376:20190762. [PMID: 33550949 PMCID: PMC7935107 DOI: 10.1098/rstb.2019.0762] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/23/2020] [Indexed: 12/18/2022] Open
Abstract
Transmitter signalling is the universal chemical language of any nervous system, but little is known about its early evolution. Here, we summarize data about the distribution and functions of neurotransmitter systems in basal metazoans as well as outline hypotheses of their origins. We explore the scenario that neurons arose from genetically different populations of secretory cells capable of volume chemical transmission and integration of behaviours without canonical synapses. The closest representation of this primordial organization is currently found in Placozoa, disk-like animals with the simplest known cell composition but complex behaviours. We propose that injury-related signalling was the evolutionary predecessor for integrative functions of early transmitters such as nitric oxide, ATP, protons, glutamate and small peptides. By contrast, acetylcholine, dopamine, noradrenaline, octopamine, serotonin and histamine were recruited as canonical neurotransmitters relatively later in animal evolution, only in bilaterians. Ligand-gated ion channels often preceded the establishment of novel neurotransmitter systems. Moreover, lineage-specific diversification of neurotransmitter receptors occurred in parallel within Cnidaria and several bilaterian lineages, including acoels. In summary, ancestral diversification of secretory signal molecules provides unique chemical microenvironments for behaviour-driven innovations that pave the way to complex brain functions and elementary cognition. This article is part of the theme issue 'Basal cognition: multicellularity, neurons and the cognitive lens'.
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Affiliation(s)
- Leonid L. Moroz
- Department of Neuroscience, McKnight Brain Institute and Whitney laboratory, University of Florida, 9505 Ocean shore Blvd, St Augustine, FL 32080, USA
| | - Daria Y. Romanova
- Laboratory of Cellular Neurobiology of Learning, Institute of Higher Nervous Activity and Neurophysiology of RAS, 5A Butlerova Street, Moscow 117485, Russia
| | - Andrea B. Kohn
- Department of Neuroscience, McKnight Brain Institute and Whitney laboratory, University of Florida, 9505 Ocean shore Blvd, St Augustine, FL 32080, USA
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12
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Differential Action of Connexin Hemichannel and Pannexin Channel Therapeutics for Potential Treatment of Retinal Diseases. Int J Mol Sci 2021; 22:ijms22041755. [PMID: 33578721 PMCID: PMC7916454 DOI: 10.3390/ijms22041755] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 02/02/2021] [Accepted: 02/07/2021] [Indexed: 12/15/2022] Open
Abstract
Dysregulation of retinal function in the early stages of light-induced retinal degeneration involves pannexins and connexins. These two types of proteins may contribute to channels that release ATP, leading to activation of the inflammasome pathway, spread of inflammation and retinal dysfunction. However, the effect of pannexin channel block alone or block of both pannexin channels and connexin hemichannels in parallel on retinal activity in vivo is unknown. In this study, the pannexin channel blocker probenecid and the connexin hemichannel blocker tonabersat were used in the light-damaged rat retina. Retinal function was evaluated using electroretinography (ERG), retinal structure was analyzed using optical coherence tomography (OCT) imaging and the tissue response to light-induced injury was assessed immunohistochemically with antibodies against glial fibrillary acidic protein (GFAP), Ionized calcium binding adaptor molecule 1 (Iba-1) and Connexin43 (Cx43). Probenecid did not further enhance the therapeutic effect of connexin hemichannel block in this model, but on its own improved activity of certain inner retina neurons. The therapeutic benefit of blocking connexin hemichannels was further evaluated by comparing these data against results from our previously published studies that also used the light-damaged rat retina model. The analysis showed that treatment with tonabersat alone was better than probenecid alone at restoring retinal function in the light-damaged retina model. The results assist in the interpretation of the differential action of connexin hemichannel and pannexin channel therapeutics for potential treatment of retinal diseases.
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13
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Bhat EA, Sajjad N. Human Pannexin 1 channel: Insight in structure-function mechanism and its potential physiological roles. Mol Cell Biochem 2021; 476:1529-1540. [PMID: 33394272 DOI: 10.1007/s11010-020-04002-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 11/21/2020] [Indexed: 12/15/2022]
Abstract
Pannexins, large non-gap junction super family exists in vertebrates, play multiple roles in different cellular functions through their ATP release. Panx1-mediated adenosine 5'-triphosphate (ATP) release plays a vital role in physiological and pathophysiological conditions and is known major extracellular molecule in purinergic signaling. To modulate their function in vivo, a proper regulation of channel is necessary. Post-translational modifications are considered to be some regulating mechanisms for PANX1, while PANX2, PANX3 have been uncharacterized to date. Through their significant evidences, PANXs exclude from gap junction and conduits ATP release and other cellular molecules from cells by various mechanisms. PANX1 is most extensive characterized and implicated in ATP signaling and inflammatory processes. Despite the constant advances, much significance of PANX1 in physiological processes remains elusive. Recently, various research groups along with our group have reported the Cryo-EM structure of Panx1 channel and uncovered the hidden functions in structure-function mechanism as well as to provide the clear understanding in physiological and pathophysiological roles. These research groups reported the novel heptameric structure with contains 4 transmembrane helices (TM), two extracellular loops and one intracellular loop with N and C terminus located at the intracellular side. In addition, the structure contains a large pore of which an inhibitor CBX act as a plug that blocking the passage of substrate. In this context, this review will present current mechanistic understanding in structure and function together with significant physiological roles particularly ATP release in health and disease. As such, this review emphasizes on recent functional properties associated with novel heptameric channel and demystifies channel-mediated ATP release function.
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Affiliation(s)
- Eijaz Ahmed Bhat
- Life Science Institute, Zhejiang University, Hangzhou, 310058, Zhejiang, People's Republic of China.
| | - Nasreena Sajjad
- Department of Biochemistry, University of Kashmir, Hazratbal, Jammu and Kashmir, India
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14
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Scemes E, Velíšek L, Velíšková J. Astrocyte and Neuronal Pannexin1 Contribute Distinctly to Seizures. ASN Neuro 2020; 11:1759091419833502. [PMID: 30862176 PMCID: PMC6415468 DOI: 10.1177/1759091419833502] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
ATP- and adenosine-mediated signaling are prominent types of glia–glia and glia–neuron interaction, with an imbalance of ATP/adenosine ratio leading to altered states of excitability, as seen in epileptic seizures. Pannexin1 (Panx1), a member of the gap junction family, is an ATP release channel that is expressed in astrocytes and neurons. Previous studies provided evidence supporting a role for purinergic-mediated signaling via Panx1 channels in seizures; using mice with global deletion of Panx1, it was shown that these channels contribute in maintenance of seizures by releasing ATP. However, nothing is known about the extent to which astrocyte and neuronal Panx1 might differently contribute to seizures. We here show that targeted deletion of Panx1 in astrocytes or neurons has opposing effects on acute seizures induced by kainic acid. The absence of Panx1 in astrocytes potentiates while the absence of Panx1 in neurons attenuates seizure manifestation. Immunohistochemical analysis performed in brains of these mice, revealed that adenosine kinase (ADK), an enzyme that regulates extracellular levels of adenosine, was increased only in seized GFAP-Cre:Panx1f/f mice. Pretreating mice with the ADK inhibitor, idotubercidin, improved seizure outcome and prevented the increase in ADK immunoreactivity. Together, these data suggest that the worsening of seizures seen in mice lacking astrocyte Panx1 is likely related to low levels of extracellular adenosine due to the increased ADK levels in astrocytes. Our study not only reveals an unexpected link between Panx1 channels and ADK but also highlights the important role played by astrocyte Panx1 channels in controlling neuronal activity.
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Affiliation(s)
- Eliana Scemes
- 1 Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA
| | - Libor Velíšek
- 1 Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA.,2 Departments of Neurology and Pediatrics, New York Medical College, Valhalla, NY, USA
| | - Jana Velíšková
- 1 Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA.,3 Departments of Obstetrics & Gynecology and Neurology, New York Medical College, Valhalla, NY, USA
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15
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CGRP signalling inhibits NO production through pannexin-1 channel activation in endothelial cells. Sci Rep 2019; 9:7932. [PMID: 31138827 PMCID: PMC6538758 DOI: 10.1038/s41598-019-44333-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 05/13/2019] [Indexed: 02/07/2023] Open
Abstract
Blood flow distribution relies on precise coordinated control of vasomotor tone of resistance arteries by complex signalling interactions between perivascular nerves and endothelial cells. Sympathetic nerves are vasoconstrictors, whereas endothelium-dependent NO production provides a vasodilator component. In addition, resistance vessels are also innervated by sensory nerves, which are activated during inflammation and cause vasodilation by the release of calcitonin gene-related peptide (CGRP). Inflammation leads to superoxide anion (O2• -) formation and endothelial dysfunction, but the involvement of CGRP in this process has not been evaluated. Here we show a novel mechanistic relation between perivascular sensory nerve-derived CGRP and the development of endothelial dysfunction. CGRP receptor stimulation leads to pannexin-1-formed channel opening and the subsequent O2• --dependent connexin-based hemichannel activation in endothelial cells. The prolonged opening of these channels results in a progressive inhibition of NO production. These findings provide new therapeutic targets for the treatment of the inflammation-initiated endothelial dysfunction.
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16
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Sánchez A, Castro C, Flores DL, Gutiérrez E, Baldi P. Gap Junction Channels of Innexins and Connexins: Relations and Computational Perspectives. Int J Mol Sci 2019; 20:E2476. [PMID: 31109150 PMCID: PMC6566657 DOI: 10.3390/ijms20102476] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 05/04/2019] [Accepted: 05/14/2019] [Indexed: 12/16/2022] Open
Abstract
Gap junction (GJ) channels in invertebrates have been used to understand cell-to-cell communication in vertebrates. GJs are a common form of intercellular communication channels which connect the cytoplasm of adjacent cells. Dysregulation and structural alteration of the gap junction-mediated communication have been proven to be associated with a myriad of symptoms and tissue-specific pathologies. Animal models relying on the invertebrate nervous system have exposed a relationship between GJs and the formation of electrical synapses during embryogenesis and adulthood. The modulation of GJs as a therapeutic and clinical tool may eventually provide an alternative for treating tissue formation-related diseases and cell propagation. This review concerns the similarities between Hirudo medicinalis innexins and human connexins from nucleotide and protein sequence level perspectives. It also sets forth evidence of computational techniques applied to the study of proteins, sequences, and molecular dynamics. Furthermore, we propose machine learning techniques as a method that could be used to study protein structure, gap junction inhibition, metabolism, and drug development.
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Affiliation(s)
- Alejandro Sánchez
- Facultad de Ciencias, Universidad Autónoma de Baja California, Ensenada, Baja California 22860, Mexico.
| | - Carlos Castro
- Facultad of Ingeniería, Arquitectura y Diseño, Universidad Autónoma de Baja California, Ensenada, Baja California 22860, Mexico.
| | - Dora-Luz Flores
- Facultad of Ingeniería, Arquitectura y Diseño, Universidad Autónoma de Baja California, Ensenada, Baja California 22860, Mexico.
| | - Everardo Gutiérrez
- Facultad de Ciencias, Universidad Autónoma de Baja California, Ensenada, Baja California 22860, Mexico.
| | - Pierre Baldi
- Department of Computer Science, Institute for Genomics and Bioinformatics, and Center for Machine Learning and Intelligent Systems, University of California, Irvine, CA 92697, USA.
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17
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Enkavi G, Javanainen M, Kulig W, Róg T, Vattulainen I. Multiscale Simulations of Biological Membranes: The Challenge To Understand Biological Phenomena in a Living Substance. Chem Rev 2019; 119:5607-5774. [PMID: 30859819 PMCID: PMC6727218 DOI: 10.1021/acs.chemrev.8b00538] [Citation(s) in RCA: 196] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Indexed: 12/23/2022]
Abstract
Biological membranes are tricky to investigate. They are complex in terms of molecular composition and structure, functional over a wide range of time scales, and characterized by nonequilibrium conditions. Because of all of these features, simulations are a great technique to study biomembrane behavior. A significant part of the functional processes in biological membranes takes place at the molecular level; thus computer simulations are the method of choice to explore how their properties emerge from specific molecular features and how the interplay among the numerous molecules gives rise to function over spatial and time scales larger than the molecular ones. In this review, we focus on this broad theme. We discuss the current state-of-the-art of biomembrane simulations that, until now, have largely focused on a rather narrow picture of the complexity of the membranes. Given this, we also discuss the challenges that we should unravel in the foreseeable future. Numerous features such as the actin-cytoskeleton network, the glycocalyx network, and nonequilibrium transport under ATP-driven conditions have so far received very little attention; however, the potential of simulations to solve them would be exceptionally high. A major milestone for this research would be that one day we could say that computer simulations genuinely research biological membranes, not just lipid bilayers.
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Affiliation(s)
- Giray Enkavi
- Department
of Physics, University of
Helsinki, P.O. Box 64, FI-00014 Helsinki, Finland
| | - Matti Javanainen
- Department
of Physics, University of
Helsinki, P.O. Box 64, FI-00014 Helsinki, Finland
- Institute
of Organic Chemistry and Biochemistry of the Czech Academy
of Sciences, Flemingovo naḿesti 542/2, 16610 Prague, Czech Republic
- Computational
Physics Laboratory, Tampere University, P.O. Box 692, FI-33014 Tampere, Finland
| | - Waldemar Kulig
- Department
of Physics, University of
Helsinki, P.O. Box 64, FI-00014 Helsinki, Finland
| | - Tomasz Róg
- Department
of Physics, University of
Helsinki, P.O. Box 64, FI-00014 Helsinki, Finland
- Computational
Physics Laboratory, Tampere University, P.O. Box 692, FI-33014 Tampere, Finland
| | - Ilpo Vattulainen
- Department
of Physics, University of
Helsinki, P.O. Box 64, FI-00014 Helsinki, Finland
- Computational
Physics Laboratory, Tampere University, P.O. Box 692, FI-33014 Tampere, Finland
- MEMPHYS-Center
for Biomembrane Physics
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18
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Coherent directed movement toward food modeled in Trichoplax, a ciliated animal lacking a nervous system. Proc Natl Acad Sci U S A 2019; 116:8901-8908. [PMID: 30979806 PMCID: PMC6500112 DOI: 10.1073/pnas.1815655116] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Trichoplax adhaerens is a small, ciliated marine animal that glides on surfaces grazing upon algae, which it digests externally. It has no muscles or nervous system and only six cell types, all but two of which are embedded in its epithelium. The epithelial cells are joined by apical adherens junctions; neither tight junctions nor gap junctions are present. Monociliated epithelial cells on the lower surface propel gliding. The cilia beat regularly, but asynchronously, and transiently contact the substrate with each stroke. The animal moves in random directions in the absence of food. We show here that it exhibits chemotaxis, moving preferentially toward algae embedded in a disk of agar. We present a mathematical model to explain how coherent, directional movements could arise from the collective actions of a set of ciliated epithelial cells, each independently sensing and responding to a chemoattractant gradient. The model incorporates realistic values for viscoelastic properties of cells and produces coordinated movements and changes in body shape that resemble the actual movements of the animal. The model demonstrates that an animal can move coherently in search of food without any need for chemical signaling between cells and introduces a different approach to modeling behavior in primitive multicellular organisms.
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19
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Dispelling myths about connexins, pannexins and P2X7 in hypoxic-ischemic central nervous system. Neurosci Lett 2019; 695:76-85. [PMID: 29195910 DOI: 10.1016/j.neulet.2017.11.044] [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: 02/14/2017] [Revised: 10/07/2017] [Accepted: 11/21/2017] [Indexed: 01/17/2023]
Abstract
In membrane physiology, as in other fields, myths or speculations may be repeated so often and so widely that they are perceived as facts. To some extent, this has occurred with regard to gap junctions, hemichannels, pannexin channels and P2X7 (ionotropic receptors), especially concerning the interpretation of the individual role of these channels in hypoxic-ischemic CNS since these channels may be closed by the same pharmacological blockers. Significance of existing controversial data are highlighted and contradictory views from different groups are critically discussed herein.
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20
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Zhou KQ, Green CR, Bennet L, Gunn AJ, Davidson JO. The Role of Connexin and Pannexin Channels in Perinatal Brain Injury and Inflammation. Front Physiol 2019; 10:141. [PMID: 30873043 PMCID: PMC6400979 DOI: 10.3389/fphys.2019.00141] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 02/07/2019] [Indexed: 12/21/2022] Open
Abstract
Perinatal brain injury remains a major cause of death and life-long disability. Perinatal brain injury is typically associated with hypoxia-ischemia and/or infection/inflammation. Both hypoxia-ischemia and infection trigger an inflammatory response in the brain. The inflammatory response can contribute to brain cell loss and chronic neuroinflammation leading to neurological impairments. It is now well-established that brain injury evolves over time, and shows a striking spread from injured to previously uninjured regions of the brain. There is increasing evidence that this spread is related to opening of connexin hemichannels and pannexin channels, both of which are large conductance membrane channels found in almost all cell types in the brain. Blocking connexin hemichannels within the first 3 h after hypoxia-ischemia has been shown to improve outcomes in term equivalent fetal sheep but it is important to also understand the downstream pathways linking membrane channel opening with the development of injury in order to identify new therapeutic targets. Open membrane channels release adenosine triphosphate (ATP), and other neuroactive molecules, into the extracellular space. ATP has an important physiological role, but has also been reported to act as a damage-associated molecular pattern (DAMP) signal mediated through specific purinergic receptors and so act as a primary signal 1 in the innate immune system inflammasome pathway. More crucially, extracellular ATP is a key inflammasome signal 2 activator, with purinergic receptor binding triggering the assembly of the multi-protein inflammasome complex. The inflammasome pathway and complex formation contribute to activation of inflammatory caspases, and the release of inflammatory cytokines, including interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-18, and vascular endothelial growth factor (VEGF). We propose that the NOD-like receptor protein-3 (NLRP3) inflammasome, which has been linked to inflammatory responses in models of ischemic stroke and various inflammatory diseases, may be one mechanism by which connexin hemichannel opening especially mediates perinatal brain injury.
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Affiliation(s)
- Kelly Q Zhou
- Department of Physiology, The University of Auckland, Auckland, New Zealand
| | - Colin R Green
- Department of Ophthalmology, The University of Auckland, Auckland, New Zealand
| | - Laura Bennet
- Department of Physiology, The University of Auckland, Auckland, New Zealand
| | - Alistair J Gunn
- Department of Physiology, The University of Auckland, Auckland, New Zealand
| | - Joanne O Davidson
- Department of Physiology, The University of Auckland, Auckland, New Zealand.,Department of Ophthalmology, The University of Auckland, Auckland, New Zealand
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21
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Abstract
BACKGROUND Gap junctions (GJ) are one of the most common forms of intercellular communication. GJs are assembled from proteins that form channels connecting the cytoplasm of adjacent cells. They are considered to be the main or the only type of intercellular channels and the universal feature of all multicellular animals. Two unrelated protein families are currently considered to be involved in this function, namely, connexins and pannexins (pannexins/innexins). Pannexins were hypothesized to be the universal GJ proteins of multicellular animals, distinct from connexins that are characteristic of chordates only. Here we have revised this supposition by applying growing high throughput sequencing data from diverse metazoan species. RESULTS Pannexins were found in Chordates, Ctenophores, Cnidarians, and in the most major groups of bilateral protostomes. Yet some metazoans appear to have neither connexins nor pannexins in their genomes. We detected no connexins or pannexins/innexins homologues in representatives of all five classes of echinoderms and their closest relatives hemichordates with available genomic sequences. Despite this, our intracellular recordings demonstrate direct electrical coupling between blastomeres at the 2-cell embryo of the echinoderm (starfish Asterias rubens). In these experiments, carboxyfluorescein fluorescent dye did not diffuse between electrically coupled cells. This excludes the possibility that the observed electrical coupling is mediated by incomplete cytoplasm separation during cleavage. CONCLUSION Functional GJs are present in representatives of the clade that lack currently recognized GJ protein families. New undiscovered protein families utilized for intercellular channels are predicted. It is possible that the new type(s) of intercellular channels are present in parallel to pannexin and connexin gap junctions in animal groups, other than Echinodermata.
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Affiliation(s)
- Georgy A Slivko-Koltchik
- Kharkevich Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow, Russian Federation, 127994
| | - Victor P Kuznetsov
- Kharkevich Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow, Russian Federation, 127994
| | - Yuri V Panchin
- Kharkevich Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow, Russian Federation, 127994.
- A.N. Belozersky Institute of Physico-Chemical Biology Moscow State University, Moscow, Russian Federation, 119991.
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22
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Abstract
The connexin family of channel-forming proteins is present in every tissue type in the human anatomy. Connexins are best known for forming clustered intercellular channels, structurally known as gap junctions, where they serve to exchange members of the metabolome between adjacent cells. In their single-membrane hemichannel form, connexins can act as conduits for the passage of small molecules in autocrine and paracrine signalling. Here, we review the roles of connexins in health and disease, focusing on the potential of connexins as therapeutic targets in acquired and inherited diseases as well as wound repair, while highlighting the associated clinical challenges.
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23
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Retamal MA, Riquelme MA, Stehberg J, Alcayaga J. Connexin43 Hemichannels in Satellite Glial Cells, Can They Influence Sensory Neuron Activity? Front Mol Neurosci 2017; 10:374. [PMID: 29200997 PMCID: PMC5696352 DOI: 10.3389/fnmol.2017.00374] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 10/27/2017] [Indexed: 12/30/2022] Open
Abstract
In this review article, we summarize the current insight on the role of Connexin- and Pannexin-based channels as modulators of sensory neurons. The somas of sensory neurons are located in sensory ganglia (i.e., trigeminal and nodose ganglia). It is well known that within sensory ganglia, sensory neurons do not form neither electrical nor chemical synapses. One of the reasons for this is that each soma is surrounded by glial cells, known as satellite glial cells (SGCs). Recent evidence shows that connexin43 (Cx43) hemichannels and probably pannexons located at SGCs have an important role in paracrine communication between glial cells and sensory neurons. This communication may be exerted via the release of bioactive molecules from SGCs and their subsequent action on receptors located at the soma of sensory neurons. The glio-neuronal communication seems to be relevant for the establishment of chronic pain, hyperalgesia and pathologies associated with tissue inflammation. Based on the current literature, it is possible to propose that Cx43 hemichannels expressed in SGCs could be a novel pharmacological target for treating chronic pain, which need to be directly evaluated in future studies.
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Affiliation(s)
- Mauricio A Retamal
- Centro de Fisiología Celular e Integrativa, Facultad de Medicina, Clinica Alemana Universidad del Desarrollo, Santiago, Chile.,Department of Cell Physiology and Molecular Biophysics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Manuel A Riquelme
- Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, United States
| | - Jimmy Stehberg
- Laboratorio de Neurobiología, Centro de Investigaciones Biomedicas, Universidad Andres Bello, Santiago, Chile
| | - Julio Alcayaga
- Department of Biology, Cell Physiology Center, University of Chile, Santiago, Chile
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24
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Regulation of Skeletal Muscle Myoblast Differentiation and Proliferation by Pannexins. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 925:57-73. [PMID: 27518505 DOI: 10.1007/5584_2016_53] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Pannexins are newly discovered channels that are now recognized as mediators of adenosine triphosphate release from several cell types allowing communication with the extracellular environment. Pannexins have been associated with various physiological and pathological processes including apoptosis, inflammation, and cancer. However, it is only recently that our work has unveiled a role for Pannexin 1 and Pannexin 3 as novel regulators of skeletal muscle myoblast proliferation and differentiation. Myoblast differentiation is an ordered multistep process that includes withdrawal from the cell cycle and the expression of key myogenic factors leading to myoblast differentiation and fusion into multinucleated myotubes. Eventually, myotubes will give rise to the diverse muscle fiber types that build the complex skeletal muscle architecture essential for body movement, postural behavior, and breathing. Skeletal muscle cell proliferation and differentiation are crucial processes required for proper skeletal muscle development during embryogenesis, as well as for the postnatal skeletal muscle regeneration that is necessary for muscle repair after injury or exercise. However, defects in skeletal muscle cell differentiation and/or deregulation of cell proliferation are involved in various skeletal muscle pathologies. In this review, we will discuss the expression of pannexins and their post-translational modifications in skeletal muscle, their known functions in various steps of myogenesis, including myoblast proliferation and differentiation, as well as their possible roles in skeletal muscle development, regeneration, and diseases such as Duchenne muscular dystrophy.
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25
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Nomura T, Taruno A, Shiraishi M, Nakahari T, Inui T, Sokabe M, Eaton DC, Marunaka Y. Current-direction/amplitude-dependent single channel gating kinetics of mouse pannexin 1 channel: a new concept for gating kinetics. Sci Rep 2017; 7:10512. [PMID: 28874774 PMCID: PMC5585217 DOI: 10.1038/s41598-017-10921-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Accepted: 08/16/2017] [Indexed: 11/25/2022] Open
Abstract
The detailed single-channel gating kinetics of mouse pannexin 1 (mPanx1) remains unknown, although mPanx1 is reported to be a voltage-activated anion-selective channel. We investigated characteristics of single-channel conductances and opening and closing rates of mPanx1 using patch-clamp techniques. The unitary current of mPanx1 shows outward rectification with single-channel conductances of ~20 pS for inward currents and ~80 pS for outward currents. The channel open time for outward currents (Cl- influx) increases linearly as the amplitude of single channel currents increases, while the open time for inward currents (Cl- efflux) is constant irrespective of changes in the current amplitude, as if the direction and amplitude of the unitary current regulates the open time. This is supported by further observations that replacement of extracellular Cl- with gluconate- diminishes the inward tail current (Cl- efflux) at a membrane potential of -100 mV due to the lowered outward current (gluconate- influx) at membrane potential of 100 mV. These results suggest that the direction and rate of charge-carrier movement regulate the open time of mPanx1, and that the previously reported voltage-dependence of Panx1 channel gating is not directly mediated by the membrane potential but rather by the direction and amplitude of currents through the channel.
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Affiliation(s)
- Takeshi Nomura
- Department of Molecular Cell Physiology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, 602-8566, Japan
- Department of Bio-Ionomics, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, 602-8566, Japan
- Department of Physical Therapy, Faculty of Rehabilitation, Kyushu Nutrition Welfare University, Kitakyushu, 800-0298, Japan
| | - Akiyuki Taruno
- Department of Molecular Cell Physiology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, 602-8566, Japan
| | - Makoto Shiraishi
- Department of Molecular Cell Physiology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, 602-8566, Japan
| | - Takashi Nakahari
- Department of Molecular Cell Physiology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, 602-8566, Japan
- Department of Bio-Ionomics, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, 602-8566, Japan
- Japan Institute for Food Education and Health, St. Agnes' University, Kyoto, 602-8013, Japan
| | - Toshio Inui
- Department of Molecular Cell Physiology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, 602-8566, Japan
- Department of Bio-Ionomics, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, 602-8566, Japan
- Saisei Mirai Clinics, Moriguchi, 570-0012, Japan
| | - Masahiro Sokabe
- Mechanobiology Laboratory, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Douglas C Eaton
- Center for Cell & Molecular Signaling, Department of Physiology, Emory University School of Medicine, Atlanta, Georgia, 30322, USA
| | - Yoshinori Marunaka
- Department of Molecular Cell Physiology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, 602-8566, Japan.
- Department of Bio-Ionomics, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, 602-8566, Japan.
- Japan Institute for Food Education and Health, St. Agnes' University, Kyoto, 602-8013, Japan.
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26
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Scemes E, Velíšková J. Exciting and not so exciting roles of pannexins. Neurosci Lett 2017; 695:25-31. [PMID: 28284836 DOI: 10.1016/j.neulet.2017.03.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Revised: 03/02/2017] [Accepted: 03/06/2017] [Indexed: 01/24/2023]
Abstract
It is the current view that purinergic signaling regulates many physiological functions. Pannexin1 (Panx1), a member of the gap junction family of proteins is an ATP releasing channel that plays important physio-pathological roles in various tissues, including the CNS. Upon binding to purinergic receptors expressed in neural cells, ATP triggers cellular responses including increased cell proliferation, cell morphology changes, release of cytokines, and regulation of neuronal excitability via release of glutamate, GABA and ATP itself. Under pathological conditions such as ischemia, trauma, inflammation, and epilepsy, extracellular ATP concentrations increases drastically but the consequences of this surge is still difficult to characterize due to its rapid metabolism in ADP and adenosine, the latter having inhibitory action on neuronal activity. For seizures, for instance, the excitatory effect of ATP on neuronal activity is mainly related to its action of P2X receptors, while the inhibitory effects are related to activation of P1, adenosine receptors. Here we provide a mini review on the properties of pannexins with a main focus on Panx1 and its involvement in seizure activity. Although there are only few studies implicating Panx1 in seizures, they are illustrative of the dual role that Panx1 has on neuronal excitability.
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Affiliation(s)
- Eliana Scemes
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
| | - Jana Velíšková
- Departments of Cell Biology & Anatomy, Obstetrics & Gynecology and Neurology, New York Medical College, Valhalla, NY, 10595, USA.
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27
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Puebla C, Retamal MA, Acuña R, Sáez JC. Regulation of Connexin-Based Channels by Fatty Acids. Front Physiol 2017; 8:11. [PMID: 28174541 PMCID: PMC5258758 DOI: 10.3389/fphys.2017.00011] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 01/06/2017] [Indexed: 01/29/2023] Open
Abstract
In this mini-review, we briefly summarize the current knowledge about the effects of fatty acids (FAs) on connexin-based channels, as well as discuss the limited information about the impact FAs may have on pannexins (Panxs). FAs regulate diverse cellular functions, some of which are explained by changes in the activity of channels constituted by connexins (Cxs) or Panxs, which are known to play critical roles in maintaining the functional integrity of diverse organs and tissues. Cxs are transmembrane proteins that oligomerize into hexamers to form hemichannels (HCs), which in turn can assemble into dodecamers to form gap junction channels (GJCs). While GJCs communicate the cytoplasm of contacting cells, HCs serve as pathways for the exchange of ions and small molecules between the intra and extracellular milieu. Panxs, as well as Cx HCs, form channels at the plasma membrane that enable the interchange of molecules between the intra and extracellular spaces. Both Cx- and Panx-based channels are controlled by several post-translational modifications. However, the mechanism of action of FAs on these channels has not been described in detail. It has been shown however that FAs frequently decrease GJC-mediated cell-cell communication. The opposite effect also has been described for HC or Panx-dependent intercellular communication, where, the acute FA effect can be reversed upon washout. Additionally, changes in GJCs mediated by FAs have been associated with post-translational modifications (e.g., phosphorylation), and seem to be directly related to chemical properties of FAs (e.g., length of carbon chain and/or degree of saturation), but this possible link remains poorly understood.
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Affiliation(s)
- Carlos Puebla
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de ChileSantiago, Chile; Centro de Fisiología Celular e Integrativa, Facultad de Medicina, Clínica Alemana Universidad del DesarrolloSantiago, Chile
| | - Mauricio A Retamal
- Centro de Fisiología Celular e Integrativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo Santiago, Chile
| | - Rodrigo Acuña
- Centro de Fisiología Celular e Integrativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo Santiago, Chile
| | - Juan C Sáez
- Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de ChileSantiago, Chile; Centro Interdisciplinario de Neurociencias de Valparaíso, Intituto Milenio, Universidad de ValparaísoValparaíso, Chile
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Begandt D, Good ME, Keller AS, DeLalio LJ, Rowley C, Isakson BE, Figueroa XF. Pannexin channel and connexin hemichannel expression in vascular function and inflammation. BMC Cell Biol 2017; 18:2. [PMID: 28124621 PMCID: PMC5267334 DOI: 10.1186/s12860-016-0119-3] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Control of blood flow distribution and tissue homeostasis depend on the tight regulation of and coordination between the microvascular network and circulating blood cells. Channels formed by connexins or pannexins that connect the intra- and extracellular compartments allow the release of paracrine signals, such as ATP and prostaglandins, and thus play a central role in achieving fine regulation and coordination of vascular function. This review focuses on vascular connexin hemichannels and pannexin channels. We review their expression pattern within the arterial and venous system with a special emphasis on how post-translational modifications by phosphorylation and S-nitrosylation of these channels modulate their function and contribute to vascular homeostasis. Furthermore, we highlight the contribution of these channels in smooth muscle cells and endothelial cells in the regulation of vasomotor tone as well as how these channels in endothelial cells regulate inflammatory responses such as during ischemic and hypoxic conditions. In addition, this review will touch on recent evidence implicating a role for these proteins in regulating red blood cell and platelet function.
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Affiliation(s)
- Daniela Begandt
- Robert M Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Miranda E Good
- Robert M Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Alex S Keller
- Robert M Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Leon J DeLalio
- Robert M Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Carol Rowley
- Robert M Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Brant E Isakson
- Robert M Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.,Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Xavier F Figueroa
- Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
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Belousov AB, Fontes JD, Freitas-Andrade M, Naus CC. Gap junctions and hemichannels: communicating cell death in neurodevelopment and disease. BMC Cell Biol 2017; 18:4. [PMID: 28124625 PMCID: PMC5267333 DOI: 10.1186/s12860-016-0120-x] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Gap junctions are unique membrane channels that play a significant role in intercellular communication in the developing and mature central nervous system (CNS). These channels are composed of connexin proteins that oligomerize into hexamers to form connexons or hemichannels. Many different connexins are expressed in the CNS, with some specificity with regard to the cell types in which distinct connexins are found, as well as the timepoints when they are expressed in the developing and mature CNS. Both the main neuronal Cx36 and glial Cx43 play critical roles in neurodevelopment. These connexins also mediate distinct aspects of the CNS response to pathological conditions. An imbalance in the expression, translation, trafficking and turnover of connexins, as well as mutations of connexins, can impact their function in the context of cell death in neurodevelopment and disease. With the ever-increasing understanding of connexins in the brain, therapeutic strategies could be developed to target these membrane channels in various neurological disorders.
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Affiliation(s)
- Andrei B Belousov
- Department of Molecular & Integrative Physiology, University of Kansas Medical Center, The University of Kansas, Kansas City, KS, 66160, USA
| | - Joseph D Fontes
- Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, The University of Kansas, Kansas City, KS, 66160, USA
| | - Moises Freitas-Andrade
- Department of Cellular & Physiological Sciences, Faculty of Medicine, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Christian C Naus
- Department of Cellular & Physiological Sciences, Faculty of Medicine, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
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Song F, Sun H, Wang Y, Yang H, Huang L, Fu D, Gan J, Huang C. Pannexin3 inhibits TNF-α-induced inflammatory response by suppressing NF-κB signalling pathway in human dental pulp cells. J Cell Mol Med 2016; 21:444-455. [PMID: 27679980 PMCID: PMC5323855 DOI: 10.1111/jcmm.12988] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Accepted: 08/16/2016] [Indexed: 01/21/2023] Open
Abstract
Human dental pulp cells (HDPCs) play a crucial role in dental pulp inflammation. Pannexin 3 (Panx3), a member of Panxs (Pannexins), has been recently found to be involved in inflammation. However, the mechanism of Panx3 in human dental pulp inflammation remains unclear. In this study, the role of Panx3 in inflammatory response was firstly explored, and its potential mechanism was proposed. Immunohistochemical staining showed that Panx3 levels were diminished in inflamed human and rat dental pulp tissues. In vitro, Panx3 expression was significantly down‐regulated in HDPCs following a TNF‐α challenge in a concentration‐dependent way, which reached the lowest level at 10 ng/ml of TNF‐α. Such decrease could be reversed by MG132, a proteasome inhibitor. Unlike MG132, BAY 11‐7082, a NF‐κB inhibitor, even reinforced the inhibitory effect of TNF‐α. Quantitative real‐time PCR (qRT‐PCR) and enzyme‐linked immunosorbent assay (ELISA) were used to investigate the role of Panx3 in inflammatory response of HDPCs. TNF‐α‐induced pro‐inflammatory cytokines, interleukin (IL)‐1β and IL‐6, were significantly lessened when Panx3 was overexpressed in HDPCs. Conversely, Panx3 knockdown exacerbated the expression of pro‐inflammatory cytokines. Moreover, Western blot, dual‐luciferase reporter assay, immunofluorescence staining, qRT‐PCR and ELISA results showed that Panx3 participated in dental pulp inflammation in a NF‐κB‐dependent manner. These findings suggested that Panx3 has a defensive role in dental pulp inflammation, serving as a potential target to be exploited for the intervention of human dental pulp inflammation.
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Affiliation(s)
- Fangfang Song
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education (KLOBM), School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China
| | - Hualing Sun
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education (KLOBM), School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China
| | - Yake Wang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education (KLOBM), School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China
| | - Hongye Yang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education (KLOBM), School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China
| | - Liyuan Huang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education (KLOBM), School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China
| | - Dongjie Fu
- Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Jing Gan
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education (KLOBM), School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China
| | - Cui Huang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education (KLOBM), School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China
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Johnson RG, Le HC, Evenson K, Loberg SW, Myslajek TM, Prabhu A, Manley AM, O’Shea C, Grunenwald H, Haddican M, Fitzgerald PM, Robinson T, Cisterna BA, Sáez JC, Liu TF, Laird DW, Sheridan JD. Connexin Hemichannels: Methods for Dye Uptake and Leakage. J Membr Biol 2016; 249:713-741. [DOI: 10.1007/s00232-016-9925-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 08/22/2016] [Indexed: 01/18/2023]
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Seref-Ferlengez Z, Suadicani SO, Thi MM. A new perspective on mechanisms governing skeletal complications in type 1 diabetes. Ann N Y Acad Sci 2016; 1383:67-79. [PMID: 27571221 DOI: 10.1111/nyas.13202] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Revised: 07/11/2016] [Accepted: 07/18/2016] [Indexed: 12/29/2022]
Abstract
This review focuses on bone mechanobiology in type 1 diabetes (T1D), an area of research on diabetes-associated skeletal complications that is still in its infancy. We first provide a brief overview of the deleterious effects of diabetes on the skeleton and of the knowledge gained from studies with rodent models of T1D. Second, we discuss two specific hallmarks of T1D, low insulin and high glucose, and address the extent to which they affect skeletal health. Third, we highlight the mechanosensitive nature of bone tissue and the importance of mechanical loading for bone health. We also summarize recent advances in bone mechanobiology that implicate osteocytes as the mechanosensors and major regulatory cells in the bone. Finally, we discuss recent evidence indicating that the diabetic bone is "deaf" to mechanical loading and that osteocytes are central players in mechanisms that lead to bone loss in T1D.
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Affiliation(s)
- Zeynep Seref-Ferlengez
- Department of Orthopaedic Surgery.,Laboratories of Musculoskeletal Orthopedic Research at Einstein-Montefiore (MORE)
| | - Sylvia O Suadicani
- Laboratories of Musculoskeletal Orthopedic Research at Einstein-Montefiore (MORE).,Department of Neuroscience.,Department of Urology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York
| | - Mia M Thi
- Department of Orthopaedic Surgery.,Laboratories of Musculoskeletal Orthopedic Research at Einstein-Montefiore (MORE).,Department of Neuroscience
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Cheung WY, Fritton JC, Morgan SA, Seref-Ferlengez Z, Basta-Pljakic J, Thi MM, Suadicani SO, Spray DC, Majeska RJ, Schaffler MB. Pannexin-1 and P2X7-Receptor Are Required for Apoptotic Osteocytes in Fatigued Bone to Trigger RANKL Production in Neighboring Bystander Osteocytes. J Bone Miner Res 2016; 31:890-9. [PMID: 26553756 PMCID: PMC4915221 DOI: 10.1002/jbmr.2740] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Revised: 11/05/2015] [Accepted: 11/08/2015] [Indexed: 12/13/2022]
Abstract
Osteocyte apoptosis is required to induce intracortical bone remodeling after microdamage in animal models, but how apoptotic osteocytes signal neighboring "bystander" cells to initiate the remodeling process is unknown. Apoptosis has been shown to open pannexin-1 (Panx1) channels to release adenosine diphosphate (ATP) as a "find-me" signal for phagocytic cells. To address whether apoptotic osteocytes use this signaling mechanism, we adapted the rat ulnar fatigue-loading model to reproducibly introduce microdamage into mouse cortical bone and measured subsequent changes in osteocyte apoptosis, receptor activator of NF-κB ligand (RANKL) expression and osteoclastic bone resorption in wild-type (WT; C57Bl/6) mice and in mice genetically deficient in Panx1 (Panx1KO). Mouse ulnar loading produced linear microcracks comparable in number and location to the rat model. WT mice showed increased osteocyte apoptosis and RANKL expression at microdamage sites at 3 days after loading and increased intracortical remodeling and endocortical tunneling at day 14. With fatigue, Panx1KO mice exhibited levels of microdamage and osteocyte apoptosis identical to WT mice. However, they did not upregulate RANKL in bystander osteocytes or initiate resorption. Panx1 interacts with P2X7 R in ATP release; thus, we examined P2X7 R-deficient mice and WT mice treated with P2X7 R antagonist Brilliant Blue G (BBG) to test the possible role of ATP as a find-me signal. P2X7 RKO mice failed to upregulate RANKL in osteocytes or induce resorption despite normally elevated osteocyte apoptosis after fatigue loading. Similarly, treatment of fatigued C57Bl/6 mice with BBG mimicked behavior of both Panx1KO and P2X7 RKO mice; BBG had no effect on osteocyte apoptosis in fatigued bone but completely prevented increases in bystander osteocyte RANKL expression and attenuated activation of resorption by more than 50%. These results indicate that activation of Panx1 and P2X7 R are required for apoptotic osteocytes in fatigued bone to trigger RANKL production in neighboring bystander osteocytes and implicate ATP as an essential signal mediating this process.
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Affiliation(s)
- Wing Yee Cheung
- Department of Biomedical Engineering, City College of New York, New York, NY, USA
| | - J Christopher Fritton
- Department of Orthopaedic Surgery, New Jersey Medical School, Rutgers University, Newark, NJ, USA
| | - Stacy Ann Morgan
- Department of Biomedical Engineering, City College of New York, New York, NY, USA
| | | | - Jelena Basta-Pljakic
- Department of Biomedical Engineering, City College of New York, New York, NY, USA
| | - Mia M Thi
- Departments of Orthopaedic Surgery, Urology, and Neuroscience, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA
| | - Sylvia O Suadicani
- Departments of Orthopaedic Surgery, Urology, and Neuroscience, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA
| | - David C Spray
- Departments of Orthopaedic Surgery, Urology, and Neuroscience, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA
| | - Robert J Majeska
- Department of Biomedical Engineering, City College of New York, New York, NY, USA
| | - Mitchell B Schaffler
- Department of Biomedical Engineering, City College of New York, New York, NY, USA
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Cogliati B, Mennecier G, Willebrords J, Da Silva TC, Maes M, Pereira IVA, Crespo-Yanguas S, Hernandez-Blazquez FJ, Dagli MLZ, Vinken M. Connexins, Pannexins, and Their Channels in Fibroproliferative Diseases. J Membr Biol 2016; 249:199-213. [PMID: 26914707 DOI: 10.1007/s00232-016-9881-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 02/16/2016] [Indexed: 12/13/2022]
Abstract
Cellular and molecular mechanisms of wound healing, tissue repair, and fibrogenesis are established in different organs and are essential for the maintenance of function and tissue integrity after cell injury. These mechanisms are also involved in a plethora of fibroproliferative diseases or organ-specific fibrotic disorders, all of which are associated with the excessive deposition of extracellular matrix components. Fibroblasts, which are key cells in tissue repair and fibrogenesis, rely on communicative cellular networks to ensure efficient control of these processes and to prevent abnormal accumulation of extracellular matrix into the tissue. Despite the significant impact on human health, and thus the epidemiologic relevance, there is still no effective treatment for most fibrosis-related diseases. This paper provides an overview of current concepts and mechanisms involved in the participation of cellular communication via connexin-based pores as well as pannexin-based channels in the processes of tissue repair and fibrogenesis in chronic diseases. Understanding these mechanisms may contribute to the development of new therapeutic strategies to clinically manage fibroproliferative diseases and organ-specific fibrotic disorders.
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Affiliation(s)
- Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Brazil
| | - Gregory Mennecier
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Brazil
| | - Joost Willebrords
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Tereza Cristina Da Silva
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Brazil
| | - Michaël Maes
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
| | | | - Sara Crespo-Yanguas
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
| | | | - Maria Lúcia Zaidan Dagli
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Brazil
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
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Moroz LL, Kohn AB. Independent origins of neurons and synapses: insights from ctenophores. Philos Trans R Soc Lond B Biol Sci 2016; 371:20150041. [PMID: 26598724 PMCID: PMC4685580 DOI: 10.1098/rstb.2015.0041] [Citation(s) in RCA: 105] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/18/2015] [Indexed: 12/29/2022] Open
Abstract
There is more than one way to develop neuronal complexity, and animals frequently use different molecular toolkits to achieve similar functional outcomes. Genomics and metabolomics data from basal metazoans suggest that neural signalling evolved independently in ctenophores and cnidarians/bilaterians. This polygenesis hypothesis explains the lack of pan-neuronal and pan-synaptic genes across metazoans, including remarkable examples of lineage-specific evolution of neurogenic and signalling molecules as well as synaptic components. Sponges and placozoans are two lineages without neural and muscular systems. The possibility of secondary loss of neurons and synapses in the Porifera/Placozoa clades is a highly unlikely and less parsimonious scenario. We conclude that acetylcholine, serotonin, histamine, dopamine, octopamine and gamma-aminobutyric acid (GABA) were recruited as transmitters in the neural systems in cnidarian and bilaterian lineages. By contrast, ctenophores independently evolved numerous secretory peptides, indicating extensive adaptations within the clade and suggesting that early neural systems might be peptidergic. Comparative analysis of glutamate signalling also shows numerous lineage-specific innovations, implying the extensive use of this ubiquitous metabolite and intercellular messenger over the course of convergent and parallel evolution of mechanisms of intercellular communication. Therefore: (i) we view a neuron as a functional character but not a genetic character, and (ii) any given neural system cannot be considered as a single character because it is composed of different cell lineages with distinct genealogies, origins and evolutionary histories. Thus, when reconstructing the evolution of nervous systems, we ought to start with the identification of particular cell lineages by establishing distant neural homologies or examples of convergent evolution. In a corollary of the hypothesis of the independent origins of neurons, our analyses suggest that both electrical and chemical synapses evolved more than once.
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Affiliation(s)
- Leonid L Moroz
- The Whitney Laboratory for Marine Bioscience, 9505 Ocean Shore Boulevard, St Augustine, FL 32080, USA Department of Neuroscience and McKnight Brain Institute, University of Florida, Gainesville, FL 32611, USA
| | - Andrea B Kohn
- The Whitney Laboratory for Marine Bioscience, 9505 Ocean Shore Boulevard, St Augustine, FL 32080, USA
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Mouse Hepatitis Virus Infection Remodels Connexin43-Mediated Gap Junction Intercellular Communication In Vitro and In Vivo. J Virol 2015; 90:2586-99. [PMID: 26676788 DOI: 10.1128/jvi.02420-15] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 12/12/2015] [Indexed: 01/31/2023] Open
Abstract
UNLABELLED Gap junctions (GJs) form intercellular channels which directly connect the cytoplasm between neighboring cells to facilitate the transfer of ions and small molecules. GJs play a major role in the pathogenesis of infection-associated inflammation. Mutations of gap junction proteins, connexins (Cxs), cause dysmyelination and leukoencephalopathy. In multiple sclerosis (MS) patients and its animal model experimental autoimmune encephalitis (EAE), Cx43 was shown to be modulated in the central nervous system (CNS). The mechanism behind Cx43 alteration and its role in MS remains unexplored. Mouse hepatitis virus (MHV) infection-induced demyelination is one of the best-studied experimental animal models for MS. Our studies demonstrated that MHV infection downregulated Cx43 expression at protein and mRNA levels in vitro in primary astrocytes obtained from neonatal mouse brains. After infection, a significant amount of Cx43 was retained in endoplasmic reticulum/endoplasmic reticulum Golgi intermediate complex (ER/ERGIC) and GJ plaque formation was impaired at the cell surface, as evidenced by a reduction of the Triton X-100 insoluble fraction of Cx43. Altered trafficking and impairment of GJ plaque formation may cause the loss of functional channel formation in MHV-infected primary astrocytes, as demonstrated by a reduced number of dye-coupled cells after a scrape-loading Lucifer yellow dye transfer assay. Upon MHV infection, a significant downregulation of Cx43 was observed in the virus-infected mouse brain. This study demonstrates that astrocytic Cx43 expression and function can be modulated due to virus stress and can be an appropriate model to understand the basis of cellular mechanisms involved in the alteration of gap junction intercellular communication (GJIC) in CNS neuroinflammation. IMPORTANCE We found that MHV infection leads to the downregulation of Cx43 in vivo in the CNS. In addition, results show that MHV infection impairs Cx43 expression in addition to gap junction communication in primary astrocytes. After infection, Cx43 did not traffic normally to the membrane to form gap junction plaques, and that could be the basis of reduced functional gap junction coupling between astrocytes. This is an important first step toward understanding how viruses affect Cx43 expression and trafficking at the cellular level. This may provide a basis for understanding how structural alterations of astrocytic gap junctions can disrupt gap junction communication between other CNS cells in altered CNS environments due to infection and inflammation. More specifically, alteration of Cx43 may be the basis of the destabilization of Cx47 in oligodendrocytes seen in and around inflammatory demyelinating plaques in MS patients.
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Del Rio R, Quintanilla RA, Orellana JA, Retamal MA. Neuron-Glia Crosstalk in the Autonomic Nervous System and Its Possible Role in the Progression of Metabolic Syndrome: A New Hypothesis. Front Physiol 2015; 6:350. [PMID: 26648871 PMCID: PMC4664731 DOI: 10.3389/fphys.2015.00350] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 11/09/2015] [Indexed: 01/26/2023] Open
Abstract
Metabolic syndrome (MS) is characterized by the following physiological alterations: increase in abdominal fat, insulin resistance, high concentration of triglycerides, low levels of HDL, high blood pressure, and a generalized inflammatory state. One of the pathophysiological hallmarks of this syndrome is the presence of neurohumoral activation, which involve autonomic imbalance associated to hyperactivation of the sympathetic nervous system. Indeed, enhanced sympathetic drive has been linked to the development of endothelial dysfunction, hypertension, stroke, myocardial infarct, and obstructive sleep apnea. Glial cells, the most abundant cells in the central nervous system, control synaptic transmission, and regulate neuronal function by releasing bioactive molecules called gliotransmitters. Recently, a new family of plasma membrane channels called hemichannels has been described to allow the release of gliotransmitters and modulate neuronal firing rate. Moreover, a growing amount of evidence indicates that uncontrolled hemichannel opening could impair glial cell functions, affecting synaptic transmission and neuronal survival. Given that glial cell functions are disturbed in various metabolic diseases, we hypothesize that progression of MS may relies on hemichannel-dependent impairment of glial-to-neuron communication by a mechanism related to dysfunction of inflammatory response and mitochondrial metabolism of glial cells. In this manuscript, we discuss how glial cells may contribute to the enhanced sympathetic drive observed in MS, and shed light about the possible role of hemichannels in this process.
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Affiliation(s)
- Rodrigo Del Rio
- Centro de Investigación Biomédica, Universidad Autónoma de Chile Santiago, Chile ; Dirección de Investigación, Universidad Científica del Sur Lima, Perú
| | | | - Juan A Orellana
- Departamento de Neurología, Escuela de Medicina, Pontificia Universidad Católica de Chile Santiago, Chile
| | - Mauricio A Retamal
- Centro de Fisiología Celular e Integrativa, Facultad de Medicina. Clínica Alemana Universidad del Desarrollo Santiago, Chile
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Wang SP, Chen FY, Dong LX, Zhang YQ, Chen HY, Qiao K, Wang KJ. A novel innexin2 forming membrane hemichannel exhibits immune responses and cell apoptosis in Scylla paramamosain. FISH & SHELLFISH IMMUNOLOGY 2015; 47:485-499. [PMID: 26384843 DOI: 10.1016/j.fsi.2015.09.028] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 09/06/2015] [Accepted: 09/14/2015] [Indexed: 06/05/2023]
Abstract
Innexins are a class of transmembrane proteins that are important for embryonic development, morphogenesis and electrical synapse formation. In the present study, a novel innexin2 gene from Scylla paramamosain was named Sp-inx2 and characterized. The complete cDNA and genomic DNA sequences of Sp-inx2 were revealed. Sp-inx2 mRNA transcripts were distributed in various tissues of S. paramamosain and were most abundant in the hemocytes. The Sp-inx2 was significantly upregulated in hemocyte, gill and hepatopancreas tissues with the challenge of either Vibrio alginolyticus, Vibrio parahaemolyticus or lipopolysaccharides (LPSs) when analyzed at 3 and 6 h using quantitative real-time PCR, suggesting that it could activate an immune response against the challenge of LPSs or Vibrio species. Using the chemical inhibitors carbenoxolone and probenecid, the absorption of the fluorescent dye Lucifer yellow decreased in the primary cultured hemocytes of crabs, thus confirming that hemichannels composed of Sp-inx2 existed in the crab hemocytes. With LPS stimulation, the level of mRNA transcripts and protein expression of Sp-inx2 in the same cultured hemocytes gradually increased from 6 to 48 h, while the activity of hemichannels was down-regulated at 6 and 12 h, demonstrating that LPSs could modulate the absorption activity of hemichannels in addition to its upregulation of Sp-inx2 gene expression. Furthermore, the dye uptake rate in HeLa cells in which Sp-inx2 was ectopically expressed increased dramatically but the increase was significantly down-regulated with the addition of 50 μg mL(-1) LPS, suggesting that the LPS stimulation could effectively reduce the activity of hemichannels. Interestingly, with the ectopic expression of Sp-inx2 in HeLa and EPC cells, apoptosis spontaneously occurred in both cultured cell lines when detected using TUNEL assay. In summary, a new Sp-inx2 gene was first characterized in a marine animal S. paramamosain and it had a function associated with immune response and cell apoptosis.
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Affiliation(s)
- Shu-Ping Wang
- State Key Laboratory of Marine Environmental Science, College of Ocean & Earth Science, Xiamen University, Xiamen, Fujian, PR China
| | - Fang-Yi Chen
- State Key Laboratory of Marine Environmental Science, College of Ocean & Earth Science, Xiamen University, Xiamen, Fujian, PR China; Fujian Collaborative Innovation Center for Exploitation and Utilization of Marine Biological Resources, Xiamen University, Xiamen, Fujian, PR China; Fujian Engineering Laboratory of Marine Bioproducts and Technology, Xiamen University, Xiamen, Fujian, PR China
| | - Li-Xia Dong
- State Key Laboratory of Marine Environmental Science, College of Ocean & Earth Science, Xiamen University, Xiamen, Fujian, PR China
| | - Ya-Qun Zhang
- State Key Laboratory of Marine Environmental Science, College of Ocean & Earth Science, Xiamen University, Xiamen, Fujian, PR China
| | - Hui-Yun Chen
- State Key Laboratory of Marine Environmental Science, College of Ocean & Earth Science, Xiamen University, Xiamen, Fujian, PR China; Fujian Collaborative Innovation Center for Exploitation and Utilization of Marine Biological Resources, Xiamen University, Xiamen, Fujian, PR China; Fujian Engineering Laboratory of Marine Bioproducts and Technology, Xiamen University, Xiamen, Fujian, PR China
| | - Kun Qiao
- State Key Laboratory of Marine Environmental Science, College of Ocean & Earth Science, Xiamen University, Xiamen, Fujian, PR China
| | - Ke-Jian Wang
- State Key Laboratory of Marine Environmental Science, College of Ocean & Earth Science, Xiamen University, Xiamen, Fujian, PR China; Fujian Collaborative Innovation Center for Exploitation and Utilization of Marine Biological Resources, Xiamen University, Xiamen, Fujian, PR China; Fujian Engineering Laboratory of Marine Bioproducts and Technology, Xiamen University, Xiamen, Fujian, PR China.
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Moroz LL, Kohn AB. Unbiased View of Synaptic and Neuronal Gene Complement in Ctenophores: Are There Pan-neuronal and Pan-synaptic Genes across Metazoa? Integr Comp Biol 2015; 55:1028-49. [PMID: 26454853 DOI: 10.1093/icb/icv104] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Hypotheses of origins and evolution of neurons and synapses are controversial, mostly due to limited comparative data. Here, we investigated the genome-wide distribution of the bilaterian "synaptic" and "neuronal" protein-coding genes in non-bilaterian basal metazoans (Ctenophora, Porifera, Placozoa, and Cnidaria). First, there are no recognized genes uniquely expressed in neurons across all metazoan lineages. None of the so-called pan-neuronal genes such as embryonic lethal abnormal vision (ELAV), Musashi, or Neuroglobin are expressed exclusively in neurons of the ctenophore Pleurobrachia. Second, our comparative analysis of about 200 genes encoding canonical presynaptic and postsynaptic proteins in bilaterians suggests that there are no true "pan-synaptic" genes or genes uniquely and specifically attributed to all classes of synapses. The majority of these genes encode receptive and secretory complexes in a broad spectrum of eukaryotes. Trichoplax (Placozoa) an organism without neurons and synapses has more orthologs of bilaterian synapse-related/neuron-related genes than do ctenophores-the group with well-developed neuronal and synaptic organization. Third, the majority of genes encoding ion channels and ionotropic receptors are broadly expressed in unicellular eukaryotes and non-neuronal tissues in metazoans. Therefore, they cannot be viewed as neuronal markers. Nevertheless, the co-expression of multiple types of ion channels and receptors does correlate with the presence of neural and synaptic organization. As an illustrative example, the ctenophore genomes encode a greater diversity of ion channels and ionotropic receptors compared with the genomes of the placozoan Trichoplax and the demosponge Amphimedon. Surprisingly, both placozoans and sponges have a similar number of orthologs of "synaptic" proteins as we identified in the genomes of two ctenophores. Ctenophores have a distinct synaptic organization compared with other animals. Our analysis of transcriptomes from 10 different ctenophores did not detect recognized orthologs of synthetic enzymes encoding several classical, low-molecular-weight (neuro)transmitters; glutamate signaling machinery is one of the few exceptions. Novel peptidergic signaling molecules were predicted for ctenophores, together with the diversity of putative receptors including SCNN1/amiloride-sensitive sodium channel-like channels, many of which could be examples of a lineage-specific expansion within this group. In summary, our analysis supports the hypothesis of independent evolution of neurons and, as corollary, a parallel evolution of synapses. We suggest that the formation of synaptic machinery might occur more than once over 600 million years of animal evolution.
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Affiliation(s)
- Leonid L Moroz
- *The Whitney Laboratory for Marine Bioscience, University of Florida, 9505 Ocean Shore Blvd, St Augustine, FL 32080, USA; Department of Neuroscience, McKnight Brain Institute and Whitney Laboratory for Marine Biosciences, University of Florida, Gainesville, FL 32611, USA
| | - Andrea B Kohn
- *The Whitney Laboratory for Marine Bioscience, University of Florida, 9505 Ocean Shore Blvd, St Augustine, FL 32080, USA
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Ganjare A, Bagul N, Kathariya R, Oberoi J. ‘Cell junctions of oral mucosa’- in a nutshell. QSCIENCE CONNECT 2015. [DOI: 10.5339/connect.2015.7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Junctional complexes are specialized contacts between neighboring cells and between cells and the extracellular matrix. They play an important role in embryogenesis, growth and development, as well as being the cause of pathologies. These contacts lead to a number of different interactions that have a profound effect on cellular biology. Cell junctions are best visualized using conventional or freeze-fracture electron microscopy, which reveals the interacting plasma membranes are highly specialized in these regions.
Cell adhesion molecules (CAMs) are proteins responsible for homophillic and heterophillic adhesions. They consist of various groups, including cadherins, selectins and intergrins and they facilitate cell adhesion, cell signaling, and motility. Dysregulation of these molecules can lead to various pathologies, for example mucocutaneous diseases and invasion of cancer. This review focuses on the pathophysiology of cell junctions and related diseases.
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Affiliation(s)
- Anjali Ganjare
- 1Department of Oral Pathology and Microbiology, Dr. D. Y Patil Dental College and Hospital, Dr. D. Y Patil Vidyapeeth, Pune-18, India
| | - Neeta Bagul
- 1Department of Oral Pathology and Microbiology, Dr. D. Y Patil Dental College and Hospital, Dr. D. Y Patil Vidyapeeth, Pune-18, India
| | - Rahul Kathariya
- 2Department of Periodontics and Oral Implantology, Dr. D. Y Patil Dental College and Hospital, Dr. D.Y Patil Vidyapeeth, Pune-18, India
| | - Jyoti Oberoi
- 3Department of Preventive and Pediatric Dentistry, Dr. D. Y Patil School of Dentistry, Nerul, Navi Mumbai- 400706, India
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Abstract
Neurons are defined as polarized secretory cells specializing in directional propagation of electrical signals leading to the release of extracellular messengers - features that enable them to transmit information, primarily chemical in nature, beyond their immediate neighbors without affecting all intervening cells en route. Multiple origins of neurons and synapses from different classes of ancestral secretory cells might have occurred more than once during ~600 million years of animal evolution with independent events of nervous system centralization from a common bilaterian/cnidarian ancestor without the bona fide central nervous system. Ctenophores, or comb jellies, represent an example of extensive parallel evolution in neural systems. First, recent genome analyses place ctenophores as a sister group to other animals. Second, ctenophores have a smaller complement of pan-animal genes controlling canonical neurogenic, synaptic, muscle and immune systems, and developmental pathways than most other metazoans. However, comb jellies are carnivorous marine animals with a complex neuromuscular organization and sophisticated patterns of behavior. To sustain these functions, they have evolved a number of unique molecular innovations supporting the hypothesis of massive homoplasies in the organization of integrative and locomotory systems. Third, many bilaterian/cnidarian neuron-specific genes and 'classical' neurotransmitter pathways are either absent or, if present, not expressed in ctenophore neurons (e.g. the bilaterian/cnidarian neurotransmitter, γ-amino butyric acid or GABA, is localized in muscles and presumed bilaterian neuron-specific RNA-binding protein Elav is found in non-neuronal cells). Finally, metabolomic and pharmacological data failed to detect either the presence or any physiological action of serotonin, dopamine, noradrenaline, adrenaline, octopamine, acetylcholine or histamine - consistent with the hypothesis that ctenophore neural systems evolved independently from those in other animals. Glutamate and a diverse range of secretory peptides are first candidates for ctenophore neurotransmitters. Nevertheless, it is expected that other classes of signal and neurogenic molecules would be discovered in ctenophores as the next step to decipher one of the most distinct types of neural organization in the animal kingdom.
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Affiliation(s)
- Leonid L Moroz
- The Whitney Laboratory of Marine Biosciences and Department of Neuroscience and McKnight Brain Institute, University of Florida, FL 32080, USA. The Whitney Laboratory, University of Florida, 9505 Ocean Shore Boulevard, St. Augustine, FL 32080, USA
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Nishii K, Shibata Y, Kobayashi Y. Connexin mutant embryonic stem cells and human diseases. World J Stem Cells 2014; 6:571-578. [PMID: 25426253 PMCID: PMC4178256 DOI: 10.4252/wjsc.v6.i5.571] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Revised: 09/11/2014] [Accepted: 09/17/2014] [Indexed: 02/06/2023] Open
Abstract
Intercellular communication via gap junctions allows cells within multicellular organisms to share small molecules. The effect of such interactions has been elucidated using mouse gene knockout strategies. Although several mutations in human gap junction-encoding connexin (Cx) have been described, Cx mutants in mice do not always recapitulate the human disease. Among the 20 mouse Cxs, Cx26, Cx43, and Cx45 play roles in early cardiac or placental development, and disruption of the genes results in lethality that hampers further analyses. Embryonic stem cells (ESCs) that lack Cx43 or Cx45 have made analysis feasible in both in vitro differentiated cell cultures and in vivo chimeric tissues. The success of mouse ESCs studies is leading to the use of induced pluripotent stem cells to learn more about the pathogenesis of human Cx diseases. This review summarizes the current status of mouse Cx disruption models and ESC differentiation studies, and discusses their implication for understanding human Cx diseases.
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Le Vasseur M, Lelowski J, Bechberger JF, Sin WC, Naus CC. Pannexin 2 protein expression is not restricted to the CNS. Front Cell Neurosci 2014; 8:392. [PMID: 25505382 PMCID: PMC4243559 DOI: 10.3389/fncel.2014.00392] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Accepted: 11/03/2014] [Indexed: 11/27/2022] Open
Abstract
Pannexins (Panx) are proteins homologous to the invertebrate gap junction proteins called innexins (Inx) and are traditionally described as transmembrane channels connecting the intracellular and extracellular compartments. Three distinct Panx paralogs (Panx1, Panx2 and Panx3) have been identified in vertebrates but previous reports on Panx expression and functionality focused primarily on Panx1 and Panx3 proteins. Several gene expression studies reported that Panx2 transcript is largely restricted to the central nervous system (CNS) hence suggesting that Panx2 might serve an important role in the CNS. However, the lack of suitable antibodies prevented the creation of a comprehensive map of Panx2 protein expression and Panx2 protein localization profile is currently mostly inferred from the distribution of its transcript. In this study, we characterized novel commercial monoclonal antibodies and surveyed Panx2 expression and distribution at the mRNA and protein level by real-time qPCR, Western blotting and immunofluorescence. Panx2 protein levels were readily detected in every tissue examined, even when transcriptional analysis predicted very low Panx2 protein expression. Furthermore, our results indicate that Panx2 transcriptional activity is a poor predictor of Panx2 protein abundance and does not correlate with Panx2 protein levels. Despite showing disproportionately high transcript levels, the CNS expressed less Panx2 protein than any other tissues analyzed. Additionally, we showed that Panx2 protein does not localize at the plasma membrane like other gap junction proteins but remains confined within cytoplasmic compartments. Overall, our results demonstrate that the endogenous expression of Panx2 protein is not restricted to the CNS and is more ubiquitous than initially predicted.
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Affiliation(s)
- Maxence Le Vasseur
- Department of Cellular and Physiological Sciences, The Life Science Institute, University of British Columbia Vancouver, BC, Canada
| | - Jonathan Lelowski
- Department of Cellular and Physiological Sciences, The Life Science Institute, University of British Columbia Vancouver, BC, Canada
| | - John F Bechberger
- Department of Cellular and Physiological Sciences, The Life Science Institute, University of British Columbia Vancouver, BC, Canada
| | - Wun-Chey Sin
- Department of Cellular and Physiological Sciences, The Life Science Institute, University of British Columbia Vancouver, BC, Canada
| | - Christian C Naus
- Department of Cellular and Physiological Sciences, The Life Science Institute, University of British Columbia Vancouver, BC, Canada
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Abstract
In less than a decade, a small family of channel-forming glycoproteins, named pannexins, have captured the interest of many biologists, in large part due to their association with common diseases, ranging from cancers to neuropathies to infectious diseases. Although the pannexin family consists of only three members (Panx1, Panx2 and Panx3), one or more of these pannexins are expressed in virtually every mammalian organ, implicating their potential role in a diverse array of pathophysiologies. Panx1 is the most extensively studied, but features of this pannexin must be cautiously extrapolated to the other pannexins, as for example we now know that Panx2, unlike Panx1, exhibits unique properties such as a tendency to be retained within intracellular compartments. In the present review, we assess the biochemical and channel features of pannexins focusing on the literature which links these unique molecules to over a dozen diseases and syndromes. Although no germ-line mutations in genes encoding pannexins have been linked to any diseases, many cases have shown that high pannexin expression is associated with disease onset and/or progression. Disease may also occur, however, when pannexins are underexpressed, highlighting that pannexin expression must be exquisitely regulated. Finally, we discuss some of the most pressing questions and controversies in the pannexin field as the community seeks to uncover the full biological relevance of pannexins in healthy organs and during disease.
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45
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Schalper KA, Carvajal-Hausdorf D, Oyarzo MP. Possible role of hemichannels in cancer. Front Physiol 2014; 5:237. [PMID: 25018732 PMCID: PMC4073485 DOI: 10.3389/fphys.2014.00237] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Accepted: 06/09/2014] [Indexed: 12/12/2022] Open
Abstract
In humans, connexins (Cxs) and pannexins (Panxs) are the building blocks of hemichannels. These proteins are frequently altered in neoplastic cells and have traditionally been considered as tumor suppressors. Alteration of Cxs and Panxs in cancer cells can be due to genetic, epigenetic and post-transcriptional/post-translational events. Activated hemichannels mediate the diffusional membrane transport of ions and small signaling molecules. In the last decade hemichannels have been shown to participate in diverse cell processes including the modulation of cell proliferation and survival. However, their possible role in tumor growth and expansion remains largely unexplored. Herein, we hypothesize about the possible role of hemichannels in carcinogenesis and tumor progression. To support this theory, we summarize the evidence regarding the involvement of hemichannels in cell proliferation and migration, as well as their possible role in the anti-tumor immune responses. In addition, we discuss the evidence linking hemichannels with cancer in diverse models and comment on the current technical limitations for their study.
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Affiliation(s)
- Kurt A Schalper
- Servicio Anatomía Patológica, Clínica Alemana de Santiago, Facultad de Medicina Clinica Alemana Universidad del Desarrollo Santiago, Chile ; Department of Pathology, Yale School of Medicine New Haven, CT, USA
| | | | - Mauricio P Oyarzo
- Servicio Anatomía Patológica, Clínica Alemana de Santiago, Facultad de Medicina Clinica Alemana Universidad del Desarrollo Santiago, Chile
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46
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The ctenophore genome and the evolutionary origins of neural systems. Nature 2014; 510:109-14. [PMID: 24847885 PMCID: PMC4337882 DOI: 10.1038/nature13400] [Citation(s) in RCA: 472] [Impact Index Per Article: 42.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2013] [Accepted: 04/23/2014] [Indexed: 12/31/2022]
Abstract
The origins of neural systems remain unresolved. In contrast to other basal metazoans, ctenophores, or comb jellies, have both complex nervous and mesoderm-derived muscular systems. These holoplanktonic predators also have sophisticated ciliated locomotion, behaviour and distinct development. Here, we present the draft genome of Pleurobrachia bachei, Pacific sea gooseberry, together with ten other ctenophore transcriptomes and show that they are remarkably distinct from other animal genomes in their content of neurogenic, immune and developmental genes. Our integrative analyses place Ctenophora as the earliest lineage within Metazoa. This hypothesis is supported by comparative analysis of multiple gene families, including the apparent absence of HOX genes, canonical microRNA machinery, and reduced immune complement in ctenophores. Although two distinct nervous systems are well-recognized in ctenophores, many bilaterian neuron-specific genes and genes of “classical” neurotransmitter pathways either are absent or, if present, are not expressed in neurons. Our metabolomic and physiological data are consistent with the hypothesis that ctenophore neural systems, and possibly muscle specification, evolved independently from those in other animals.
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47
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Gaynullina D, Tarasova OS, Kiryukhina OO, Shestopalov VI, Panchin Y. Endothelial function is impaired in conduit arteries of pannexin1 knockout mice. Biol Direct 2014; 9:8. [PMID: 24885326 PMCID: PMC4046076 DOI: 10.1186/1745-6150-9-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Accepted: 05/14/2014] [Indexed: 11/21/2022] Open
Abstract
Pannexin1 is ubiquitously expressed in vertebrate tissues, but the role it plays in vascular tone regulation remains unclear. We found that Pannexin1 expression level is much higher in the endothelium relative to smooth muscle of saphenous artery. The ability of endothelium-intact arteries for dilation was significantly impaired whereas contractile responses were considerably increased in mice with genetic ablation of Pannexin1. No such increased contractile responses were detected in the endothelium-denuded arteries. Combined, our findings suggest a new function of Pannexin1 as an important player in normal endothelium-dependent regulation of arterial tone, where it facilitates vessel dilation and attenuates constriction. Reviewed by Dr. Armen Mulkidjanian and Dr. Alexander Lobkovsky.
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Affiliation(s)
- Dina Gaynullina
- Department of Human and Animal Physiology, Faculty of Biology, M,V, Lomonosov Moscow State University, Leninskie Gory 1-12, 119234 Moscow, Russia.
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Pannexins form gap junctions with electrophysiological and pharmacological properties distinct from connexins. Sci Rep 2014; 4:4955. [PMID: 24828343 PMCID: PMC4021813 DOI: 10.1038/srep04955] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Accepted: 04/22/2014] [Indexed: 11/17/2022] Open
Abstract
Stable expression of pannexin 1 (Panx1) and pannexin 3 (Panx3) resulted in functional gap junctions (GJs) in HeLa cells, but not in Neuro-2a (N2a) or PC-12 cells. The glycosylation pattern of expressed Panx1 varied greatly among different cell lines. In contrast to connexin (Cx) containing GJs (Cx-GJs), junctional conductance (Gj) of pannexin GJs (Panx-GJs) is very less sensitive to junctional voltage. Both Panx1 and Panx3 junctions favoured anionic dyes over cations to permeate. Though, carbenoxolone (CBX) and probenecid blocked Panx1 hemichannel activity, they had no effect on Panx1-GJs or Panx3-GJs. Extracellular loop 1 (E1) of Panx1 possibly bears the binding pocket. The Cx-GJ blocker heptanol blocked neither Panx1 hemichannel nor Panx-GJs. Unlike the GJs formed by most Cxs, CO2 did not uncouple Panx-GJs completely. Oxygen and glucose deprivation (OGD) caused lesser uncoupling of Panx-GJs compared to Cx43-GJs. These findings demonstrate properties of Panx-GJs that are distinctly different from Cx-GJs.
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49
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Makarenkova HP, Shestopalov VI. The role of pannexin hemichannels in inflammation and regeneration. Front Physiol 2014; 5:63. [PMID: 24616702 PMCID: PMC3933922 DOI: 10.3389/fphys.2014.00063] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Accepted: 02/02/2014] [Indexed: 12/19/2022] Open
Abstract
Tissue injury involves coordinated systemic responses including inflammatory response, targeted cell migration, cell-cell communication, stem cell activation and proliferation, and tissue inflammation and regeneration. The inflammatory response is an important prerequisite for regeneration. Multiple studies suggest that extensive cell-cell communication during tissue regeneration is coordinated by purinergic signaling via extracellular adenosine triphosphate (ATP). Most recent data indicates that ATP release for such communication is mediated by hemichannels formed by connexins and pannexins. The Pannexin family consists of three vertebrate proteins (Panx 1, 2, and 3) that have low sequence homology with other gap junction proteins and were shown to form predominantly non-junctional plasma membrane hemichannels. Pannexin-1 (Panx1) channels function as an integral component of the P2X/P2Y purinergic signaling pathway and is arguably the major contributor to pathophysiological ATP release. Panx1 is expressed in many tissues, with highest levels detected in developing brain, retina and skeletal muscles. Panx1 channel expression and activity is reported to increase significantly following injury/inflammation and during regeneration and differentiation. Recent studies also report that pharmacological blockade of the Panx1 channel or genetic ablation of the Panx1 gene cause significant disruption of progenitor cell migration, proliferation, and tissue regeneration. These findings suggest that pannexins play important roles in activation of both post-injury inflammatory response and the subsequent process of tissue regeneration. Due to wide expression in multiple tissues and involvement in diverse signaling pathways, pannexins and connexins are currently being considered as therapeutic targets for traumatic brain or spinal cord injuries, ischemic stroke and cancer. The precise role of pannexins and connexins in the balance between tissue inflammation and regeneration needs to be further understood.
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Affiliation(s)
- Helen P Makarenkova
- Department of Cell and Molecular Biology, The Scripps Research Institute La Jolla, CA, USA
| | - Valery I Shestopalov
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine Miami, FL, USA ; Department of Cell Biology and Anatomy, Vavilov Institute for General Genetics Moscow, Russia
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50
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Abstract
The pannexins (Panxs) are a family of chordate proteins homologous to the invertebrate gap junction forming proteins named innexins. Three distinct Panx paralogs (Panx1, Panx2, and Panx3) are shared among the major vertebrate phyla, but they appear to have suppressed (or even lost) their ability to directly couple adjacent cells. Connecting the intracellular and extracellular compartments is now widely accepted as Panx's primary function, facilitating the passive movement of ions and small molecules along electrochemical gradients. The tissue distribution of the Panxs ranges from pervasive to very restricted, depending on the paralog, and are often cell type-specific and/or developmentally regulated within any given tissue. In recent years, Panxs have been implicated in an assortment of physiological and pathophysiological processes, particularly with respect to ATP signaling and inflammation, and they are now considered to be a major player in extracellular purinergic communication. The following is a comprehensive review of the Panx literature, exploring the historical events leading up to their discovery, outlining our current understanding of their biochemistry, and describing the importance of these proteins in health and disease.
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Affiliation(s)
- Stephen R Bond
- Genome Technology Branch, Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health Bethesda, MD, USA ; Department of Cellular and Physiological Science, Life Sciences Institute, University of British Columbia Vancouver, BC, Canada
| | - Christian C Naus
- Department of Cellular and Physiological Science, Life Sciences Institute, University of British Columbia Vancouver, BC, Canada
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