• Ca2+ signalling
• Carcinoma
• Epithelial-mesenchymal transition
• Necroptosis
• RIPK1
• ROS
• Tumour microenvironment
• pH sensor

• Humans
• Acid Sensing Ion Channels/metabolism
• Protons
• Signal Transduction
• Neurons/metabolism
• Neoplasms
• Tumor Microenvironment

• RWTH Aachen University (3131)

• Humans
• Epithelial Sodium Channels/metabolism
• Epithelial Sodium Channels/physiology
• Animals

• U54 DK137329 NIDDK NIH HHS
• P30 DK079307 NIDDK NIH HHS
• R01 DK129285 NIDDK NIH HHS
• R01 DK125439 NIDDK NIH HHS
• R01 HL147818 NHLBI NIH HHS

• ENaC
• bile acids
• gut microbiome
• salt-sensitive hypertension

• Bile Acids and Salts
• Gastrointestinal Microbiome/physiology
• Humans
• Hypertension/chemically induced
• Liver
• Sodium Chloride, Dietary/adverse effects

• R01 HL144941 NHLBI NIH HHS
• R03 HL155041 NHLBI NIH HHS
• UL1 TR002243 NCATS NIH HHS
• American Heart Association (AHA)
• Georgia Clinical and Translational Science Alliance (CTSA)
• HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)

• FXR
• TGR5
• bile acid
• motility
• secretion

• Bile Acids and Salts/metabolism
• Gastrointestinal Tract/drug effects
• Humans
• Ion Channels/agonists
• Ion Channels/drug effects
• Liver/drug effects
• Receptors, Calcitriol/drug effects
• Sodium Channels/drug effects

• R01 DE026806 NIDCR NIH HHS
• R01 DK118971 NIDDK NIH HHS
• R01 NS102722 NINDS NIH HHS
• R01 DE029951 NIDCR NIH HHS
• University of Erlangen-Nuremberg
• Department of Health, Australian Government | NHMRC | National Institute for Dementia Research (NNIDR)
• HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
• HHS | NIH | National Institute of Dental and Craniofacial Research (NIDCR)
• HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Science Foundation Ireland (SFI)
• U.S. Department of Defense (DOD)
• Australian Research Council

The bile acid-sensitive ion channel (BASIC) is a member of the Deg/ENaC family of ion channels that is activated by bile acids. Despite the identification of cholangiocytes in the liver and unipolar brush cells in the cerebellum as sites of expression, the physiological function of BASIC in these cell types is not yet understood. Here we used a cholangiocyte cell line, normal rat cholangiocytes (NRCs), which expresses BASIC to study the role of the channel in epithelial transport using Ussing chamber experiments. Apical application of bile acids induced robust and transient increases in transepithelial currents that were carried by Na⁺ and partly blocked by the BASIC inhibitor diminazene. Genetic ablation of the BASIC gene in NRC using a CRISPR-cas9 approach resulted in a decrease of the bile acid-mediated response that matched the diminazene-sensitive current in NRC WT cells, suggesting that cholangiocytes respond to bile acids with a BASIC-mediated Na⁺ influx. Taken together, we have identified BASIC as a component of the cholangiocyte transport machinery, which might mediate a bile acid-dependent modification of the bile and thus control bile flux and composition.

• BASIC
• BLINaC
• Bile acid
• Cation channel
• Cholangiocyte
• Deg/ENaC

• Bile acid sensitive ion channel
• Carbonic anhydrase
• Cholestasis
• SLC transporter
• Secretory epithelia
• Type 5 protein tyrosine phosphatase receptor

• MEC-6
• PON3
• aldosterone
• chaperone
• degenerin
• epithelial sodium channel (ENaC)
• hypertension
• kidney

Unipolar brush cells (UBCs) are excitatory granular layer interneurons in the vestibulocerebellum. Here we assessed motor coordination and balance to investigate if deletion of acid-sensing ion channel 5 (Asic5), which is richly expressed in type II UBCs, is sufficient to cause ataxia. The possible cellular mechanism underpinning ataxia in this global Asic5 knockout model was elaborated using brain slice electrophysiology. Asic5 deletion impaired motor performance and decreased intrinsic UBC excitability, reducing spontaneous action potential firing by slowing maximum depolarization rate. Reduced intrinsic excitability in UBCs was partially compensated by suppression of the magnitude and duration of delayed hyperpolarizing K⁺ currents triggered by glutamate. Glutamate typically stimulates burst firing subsequent to this hyperpolarization in normal type II UBCs. Burst firing frequency was elevated in knockout type II UBCs because it was initiated from a more depolarized potential compared to normal cells. Findings indicate that Asic5 is important for type II UBC activity and that loss of Asic5 contributes to impaired movement, likely, at least in part, due to altered temporal processing of vestibular input.

• allosteric regulation
• bile acid
• bililrubin
• cholic acid
• degenerin family
• epithelial sodium channel (ENaC)
• kidney tubule
• physico-chemical properties
• protein palmitoylation
• proteolysis
• renal physiology
• trimeric cation channel

• Animals
• Antioxidants/pharmacology
• Bile Acids and Salts/pharmacology
• Bilirubin/pharmacology
• Cholagogues and Choleretics/pharmacology
• Deoxycholic Acid/pharmacology
• Epithelial Sodium Channels/genetics
• Epithelial Sodium Channels/metabolism
• Gastrointestinal Agents/pharmacology
• Gene Expression Regulation/drug effects
• Humans
• Ion Transport
• Lipoylation
• Mice
• Oocytes/cytology
• Oocytes/drug effects
• Oocytes/metabolism
• Proteolysis
• Sodium/metabolism
• Xenopus laevis

• K08 DK110332 NIDDK NIH HHS
• P30 DK079307 NIDDK NIH HHS
• R01 DK098204 NIDDK NIH HHS
• R01 DK125439 NIDDK NIH HHS
• HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

• Bile acid
• Cation channel
• P2X

Acid-sensing ion channels (ASICs) belong to the DEG/ENaC gene family. While ASIC1a, ASIC1b and ASIC3 are activated by extracellular protons, ASIC4 and the closely related bile acid-sensitive ion channel (BASIC or ASIC5) are orphan receptors. Neuropeptides are important modulators of ASICs. Moreover, related DEG/ENaCs are directly activated by neuropeptides, rendering neuropeptides interesting ligands of ASICs. Here, we performed an unbiased screen of 109 short neuropeptides (<20 amino acids) on five homomeric ASICs: ASIC1a, ASIC1b, ASIC3, ASIC4 and BASIC. This screen revealed no direct agonist of any ASIC but three modulators. First, dynorphin A as a modulator of ASIC1a, which increased currents of partially desensitized channels; second, YFMRFamide as a modulator of ASIC1b and ASIC3, which decreased currents of ASIC1b and slowed desensitization of ASIC1b and ASIC3; and, third, endomorphin-1 as a modulator of ASIC3, which also slowed desensitization. With the exception of YFMRFamide, which, however, is not a mammalian neuropeptide, we identified no new modulator of ASICs. In summary, our screen confirmed some known peptide modulators of ASICs but identified no new peptide ligands of ASICs, suggesting that most short peptides acting as ligands of ASICs are already known.

• ASIC
• BASIC
• Bile acid
• Cation channel
• ENaC

Acid‐sensing ion channels (ASICs) are nonvoltage‐gated sodium channels transiently activated by extracellular protons and belong to the epithelial sodium channel (ENaC)/Degenerin (DEG) family of ion channels. Bile acids have been shown to activate two members of this family, the bile acid‐sensitive ion channel (BASIC) and ENaC. To investigate whether bile acids also modulate ASIC function, human ASIC1a was heterologously expressed in Xenopus laevis oocytes. Exposing oocytes to tauro‐conjugated cholic (t‐CA), deoxycholic (t‐DCA), and chenodeoxycholic (t‐CDCA) acid at pH 7.4 did not activate ASIC1a‐mediated whole‐cell currents. However, in ASIC1a expressing oocytes the whole‐cell currents elicited by pH 5.5 were significantly increased in the presence of these bile acids. Single‐channel recordings in outside‐out patches confirmed that t‐DCA enhanced the stimulatory effect of pH 5.5 on ASIC1a channel activity. Interestingly, t‐DCA reduced single‐channel current amplitude by ~15% which suggests an interaction of t‐DCA with a region close to the channel pore. Molecular docking predicted binding of bile acids to the pore region near the degenerin site (G433) in the open conformation of the channel. Site‐directed mutagenesis demonstrated that the amino acid residue G433 is critically involved in the potentiating effect of bile acids on ASIC1a activation by protons.

• Acid‐sensing ion channel 1a (ASIC1a)
• bile acids
• degenerin site
• patch clamp

• BASIC
• Bile acids
• Ca2+
• Degenerin site
• Molecular dynamics (MD) simulations
• Tauro-deoxycholic acid

• ASIC
• Acid-sensing ion channels
• Alzheimer’s disease
• acidity
• cognitive function
• pH
• protons

• Acid Sensing Ion Channels/metabolism
• Alzheimer Disease/metabolism
• Animals
• Brain/metabolism
• Humans
• Protons

• P01 AG027956 NIA NIH HHS

• BASIC
• BLINaC
• Deg/ENaC
• X-ray scattering
• Xenopus
• amphiphilic helix
• bile acid
• cholesterol
• ion channel
• patch clamp

• ENaC activation
• MTSET
• Xenopus
• bile acid
• degenerin site
• electrophysiology
• epithelial sodium channel (ENaC)
• ion channel
• oocyte
• patch clamp

• ASIC
• Degenerin
• ENaC
• Evolution
• Ligand-gated ion channel
• Nervous system
• Neuropeptide

• AKR1C3 inhibitor
• Bile acid-sensitive ion channel
• Computational conformational analyses
• Flufenamic acid
• Ion channel modulator
• Pentafluorosulfanyl group

• 3-Hydroxysteroid Dehydrogenases/antagonists & inhibitors
• 3-Hydroxysteroid Dehydrogenases/metabolism
• Aldo-Keto Reductase Family 1 Member C3
• Cyclooxygenase 1/metabolism
• Cyclooxygenase 2/metabolism
• Dose-Response Relationship, Drug
• Enzyme Inhibitors/chemical synthesis
• Enzyme Inhibitors/chemistry
• Enzyme Inhibitors/pharmacology
• Flufenamic Acid/chemical synthesis
• Flufenamic Acid/chemistry
• Flufenamic Acid/pharmacology
• Humans
• Hydroxyprostaglandin Dehydrogenases/antagonists & inhibitors
• Hydroxyprostaglandin Dehydrogenases/metabolism
• Molecular Structure
• Structure-Activity Relationship
• Sulfhydryl Compounds/chemistry

• P01 CA163227 NCI NIH HHS
• P30 ES013508 NIEHS NIH HHS
• P01-CA163227-03 NCI NIH HHS
• P30-ES013508 NIEHS NIH HHS

• ASIC
• Cortical spreading depression
• Dura
• Headache
• Meninges
• Migraine

• Acid Sensing Ion Channel Blockers/pharmacology
• Acid Sensing Ion Channel Blockers/therapeutic use
• Acid Sensing Ion Channels/metabolism
• Animals
• Cortical Spreading Depression/drug effects
• Cortical Spreading Depression/physiology
• Humans
• Migraine Disorders/drug therapy
• Migraine Disorders/metabolism

• R01 GM102575 NIGMS NIH HHS
• R01 NS072204 NINDS NIH HHS
• GM102575 NIGMS NIH HHS
• NS072204 NINDS NIH HHS

In many cells, bile acids (BAs) have a multitude of effects, some of which may be mediated by specific receptors such the TGR5 or FXR receptors. In pancreas systemic BAs, as well as intra-ductal BAs from bile reflux, can affect pancreatic secretion. Extracellular ATP and purinergic signalling are other important regulators of similar secretory mechanisms in pancreas. The aim of our study was to elucidate whether there is interplay between ATP and BA signalling.

Here we show that CDCA (chenodeoxycholic acid) caused fast and concentration-dependent ATP release from acini (AR42J) and duct cells (Capan-1). Taurine and glycine conjugated forms of CDCA had smaller effects on ATP release in Capan-1 cells. In duct monolayers, CDCA stimulated ATP release mainly from the luminal membrane; the releasing mechanisms involved both vesicular and non-vesicular secretion pathways. Duct cells were not depleted of intracellular ATP with CDCA, but acinar cells lost some ATP, as detected by several methods including ATP sensor AT1.03^YEMK. In duct cells, CDCA caused reversible increase in the intracellular Ca²⁺ concentration [Ca^{2 +}]_i, which could be significantly inhibited by antagonists of purinergic receptors. The TGR5 receptor, expressed on the luminal side of pancreatic ducts, was not involved in ATP release and Ca²⁺ signals, but could stimulate Na⁺/Ca²⁺ exchange in some conditions.

CDCA evokes significant ATP release that can stimulate purinergic receptors, which in turn increase [Ca²⁺]_i. The TGR5 receptor is not involved in these processes but can play a protective role at high intracellular Ca²⁺ conditions. We propose that purinergic signalling could be taken into consideration in other cells/organs, and thereby potentially explain some of the multifaceted effects of BAs.

The online version of this article (doi:10.1186/s12964-015-0107-9) contains supplementary material, which is available to authorized users.

• Acid surveillance
• Acid-induced pain
• Acid-related gastrointestinal diseases
• Acid-sensing ion channels
• Gastrointestinal tract
• Inflammation
• Primary afferent neurons
• Proton-gated currents
• Visceral hypersensitivity

• Acid Sensing Ion Channels/metabolism
• Animals
• Gastrointestinal Tract/metabolism
• Humans
• Inflammation/metabolism
• Pain/metabolism

• P 23097 Austrian Science Fund FWF
• P 25912 Austrian Science Fund FWF

• Acid Sensing Ion Channel Blockers/pharmacology
• Acid Sensing Ion Channels/chemistry
• Acid Sensing Ion Channels/drug effects
• Acid Sensing Ion Channels/metabolism
• Amino Acid Sequence
• Animals
• Epithelial Sodium Channel Blockers/pharmacology
• Epithelial Sodium Channels/chemistry
• Epithelial Sodium Channels/drug effects
• Epithelial Sodium Channels/metabolism
• Humans
• Hydrogen-Ion Concentration
• Ion Channel Gating/drug effects
• Ligands
• Phylogeny
• Protein Conformation
• Sequence Homology, Amino Acid
• Signal Transduction/drug effects
• Sodium/metabolism
• Structure-Activity Relationship

The bile acid-sensitive ion channel (BASIC) is a member of the DEG/ENaC family of ion channels. Channels of this family are characterized by a common structure, their physiological functions and modes of activation, however, are diverse. Rat BASIC is expressed in brain, liver and intestinal tract and activated by bile acids. The physiological function of BASIC and its mechanism of bile acid activation remain a puzzle. Here we addressed the question whether amphiphilic bile acids activate BASIC by directly binding to the channel or indirectly by altering the properties of the surrounding membrane. We show that membrane-active substances other than bile acids also affect the activity of BASIC and that activation by bile acids and other membrane-active substances is non-additive, suggesting that BASIC is sensitive for changes in its membrane environment. Furthermore based on results from chimeras between BASIC and ASIC1a, we show that the extracellular and the transmembrane domains are important for membrane sensitivity.

• Acid Sensing Ion Channels/chemistry
• Acid Sensing Ion Channels/metabolism
• Animals
• Bile Acids and Salts/pharmacology
• Cell Membrane/drug effects
• Cell Membrane/metabolism
• Chlorpromazine/pharmacology
• Cholesterol/pharmacology
• Gadolinium/pharmacology
• Ion Channel Gating/drug effects
• Mice
• Picrates/pharmacology
• Protein Structure, Tertiary
• Rats
• Structure-Activity Relationship
• Ursodeoxycholic Acid/pharmacology
• Xenopus laevis

It is generally the case that fast transmission at neural synapses is mediated by small molecule neurotransmitters. The simple nervous system of the cnidarian Hydra, however, contains a large repertoire of neuropeptides and it has been suggested that neuropeptides are the principal transmitters of Hydra. An ion channel directly gated by Hydra-RFamide neuropeptides has indeed been identified in Hydra – the Hydra Na⁺ channel (HyNaC) 2/3/5, which is expressed at the oral side of the tentacle base. Hydra-RFamides are more widely expressed, however, being found in neurons of the head and peduncle region. Here, we explore whether further peptide-gated HyNaCs exist, where in the animal they are expressed, and whether they are all gated by Hydra-RFamides.

We report molecular cloning of seven new HyNaC subunits – HyNaC6 to HyNaC12, all of which are members of the DEG/ENaC gene family. In Xenopus oocytes, these subunits assemble together with the four already known subunits into thirteen different ion channels that are directly gated by Hydra-RFamide neuropeptides with high affinity (up to 40 nM). In situ hybridization suggests that HyNaCs are expressed in epitheliomuscular cells at the oral and the aboral side of the tentacle base and at the peduncle. Moreover, diminazene, an inhibitor of HyNaCs, delayed tentacle movement in live Hydra.

Our results show that Hydra has a large variety of peptide-gated ion channels that are activated by a restricted number of related neuropeptides. The existence and expression pattern of these channels, and behavioral effects induced by channel blockers, suggests that Hydra co-opted neuropeptides for fast neuromuscular transmission.

The online version of this article (doi:10.1186/s12915-014-0084-2) contains supplementary material, which is available to authorized users.

Chronic inflammatory pain resulting from arthritis, nerve injury and tumor growth is a serious public health issue. One of the major challenges in chronic inflammatory pain research is to develop new pharmacologic treatments with long-term efficacy and few side effects. The mediators released from inflamed sites induce complex changes in peripheral and central processing by directly acting on transducer receptors located on primary sensory neurons to transmit pain signals or indirectly modulating pain signals by activating receptors coupled with G-proteins and second messengers. High local proton concentration (acidosis) is thought to be a decisive factor in inflammatory pain and other mediators such as prostaglandin, bradykinin, and serotonin enhance proton-induced pain. Proton-sensing ion channels [transient receptor potential V1 (TRPV1) and the acid-sensing ion channel (ASIC) family] are major receptors for direct excitation of nociceptive sensory neurons in response to acidosis or inflammation. G-protein-coupled receptors activated by prostaglandin, bradykinin, serotonin, and proton modulate functions of TRPV1, ASICs or other ion channels, thus leading to inflammation- or acidosis-linked hyperalgesia. Although detailed mechanisms remain unsolved, clearly different types of pain or hyperalgesia could be due to complex interactions between a distinct subset of inflammatory mediator receptors expressed in a subset of nociceptors. This review describes new directions for the development of novel therapeutic treatments in pain.

• Acid-sensing ion channel
• Acidosis
• G-protein-coupled receptor
• Inflammation
• Proton-sensing ion channel
• Transient receptor potential V1

Acid-sensing ion channels (Asic) are ligand-gated ion channels in the Degenerin/Epithelial Na⁺ channel (Deg/ENaC) family. Asic proteins are richly expressed in mammalian neurons. Mammals express five Asic genes: Asic1-5. The gene product of Asic5 is an orphan member of the family about which little is known. To investigate Asic5 expression, we created an Asic5 reporter mouse. We find that Asic5 is chiefly expressed in the brain in the cerebellum, specifically in the ventral uvula and nodulus of the vestibulocerebellum. Here, Asic5 is restrictively expressed in a subset of interneurons in the granular layer. The locale, distinctive shape and immunohistochemical properties of these Asic5-expressing interneurons identify them as unipolar brush cells (UBC). Asic5 is richly expressed in a subset of UBCs that also express the metabotropic glutamate receptor 1α (mGluR1α) but not those that express calretinin. Results from single cell RT-PCR and electrophysiological examination of these cells are consistent with this identity. Such observations are consistent with Asic5 playing a key role in the physiology of UBCs and in the function of the vestibulocerebellum.

• Acid Sensing Ion Channels/genetics
• Animals
• Cell Polarity
• Cerebellum/cytology
• Cerebellum/physiology
• Electrophysiological Phenomena
• Gene Expression Regulation
• Interneurons/metabolism
• Mice
• Receptors, Metabotropic Glutamate/metabolism

• P30 CA54174 NCI NIH HHS
• P01AG19316 NIA NIH HHS
• P01 AG019316 NIA NIH HHS
• P30 AG013319 NIA NIH HHS
• P30 CA054174 NCI NIH HHS

• ASIC
• BASIC
• BLINaC
• DEG/ENaC
• ENaC
• acid-sensing ion channel
• bile acid
• cholangiocyte
• epithelial Na+ channel

Degenerin/epithelial Na⁺ channels (DEG/ENaCs) are Na⁺ channels that are blocked by the diuretic amiloride. In general, they are impermeable for Ca²⁺ or have a very low permeability for Ca²⁺. We describe here, however, that a DEG/ENaC from the cnidarian Hydra magnipapillata, the Hydra Na⁺ channel (HyNaC), is highly permeable for Ca²⁺ (P_Ca/P_Na = 3.8). HyNaC is directly gated by Hydra neuropeptides, and in Xenopus laevis oocytes expressing HyNaCs, RFamides elicit currents with biphasic kinetics, with a fast transient component and a slower sustained component. Although it was previously reported that the sustained component is unselective for monovalent cations, the selectivity of the transient component had remained unknown. Here, we show that the transient current component arises from secondary activation of the Ca²⁺-activated Cl⁻ channel (CaCC) of Xenopus oocytes. Inhibiting the activation of the CaCC leads to a simple on–off response of peptide-activated currents with no apparent desensitization. In addition, we identify a conserved ring of negative charges at the outer entrance of the HyNaC pore that is crucial for the high Ca²⁺ permeability, presumably by attracting divalent cations to the pore. At more positive membrane potentials, the binding of Ca²⁺ to the ring of negative charges increasingly blocks HyNaC currents. Thus, HyNaC is the first member of the DEG/ENaC gene family with a high Ca²⁺ permeability.

Bile acid-sensitive ion channel (BASIC) is a member of the DEG/ENaC gene family of unknown function. Rat BASIC (rBASIC) is inactive at rest. We have recently shown that cholangiocytes, the epithelial cells lining the bile ducts, are the main site of BASIC expression in the liver and identified bile acids, in particular hyo- and chenodeoxycholic acid, as agonists of rBASIC. Moreover, it seems that extracellular divalent cations stabilize the resting state of rBASIC, because removal of extracellular divalent cations opens the channel. In this addendum, we demonstrate that removal of extracellular divalent cations potentiates the activation of rBASIC by bile acids, suggesting an allosteric mechanism. Furthermore, we show that rBASIC is strongly activated by the anticholestatic bile acid ursodeoxycholic acid (UDCA), suggesting that BASIC might mediate part of the therapeutic effects of UDCA.

• ASIC
• BASIC
• BLINaC
• DEG/ENaC
• ENaC
• acid-sensing ion channel
• bile acid
• cholangiocyte
• epithelial Na+ channel