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Last update 08 May 2025

ASIC2

Last update 08 May 2025

Basic Info

Synonyms

ACCN, ACCN1, acid sensing ion channel subunit 2

+ [14]

Introduction

Cation channel with high affinity for sodium, which is gated by extracellular protons and inhibited by the diuretic amiloride. Also permeable for Li(+) and K(+). Generates a biphasic current with a fast inactivating and a slow sustained phase. Heteromeric channel assembly seems to modulate.

Drugs associated with ASIC2

NPI-507

Target

ASIC2

Mechanism

ASIC2 inhibitors

Active Org.-

Originator Org.

Neuroprotect, Inc.

Active Indication-

Inactive Indication

Epilepsy

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

TH-901

Target

ASIC2

Mechanism

ASIC2 inhibitors

Active Org.-

Originator Org.

Theralpha S.A.S.

Active Indication-

Inactive Indication

Pain

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with ASIC2

100 Translational Medicine associated with ASIC2

0 Patents (Medical) associated with ASIC2

592

Literatures (Medical) associated with ASIC2

30 Apr 2025·The FASEB Journal

Invertebrate Bile Acid‐Sensitive Ion Channels and Their Emergence in Bilateria

Article

Author: Hejnol, Andreas ; Lynagh, Timothy ; Martí‐Solans, Josep ; Vevle, Line ; Børve, Aina

ABSTRACTThe broad Degenerin/epithelial sodium channel (DEG/ENaC) family includes a subfamily of bile acid‐sensing ion channels (BASICs). While their biophysical properties are extensively studied in mammals, the presence and function of BASICs in invertebrates remain largely unexplored. Here, we present the first functional evidence of invertebrate BASICs, revealing conserved features and evolutionary adaptations across bilaterian species. Using electrophysiological and pharmacological approaches, we show that invertebrate BASICs exhibit species‐specific bile acid sensitivity profiles and differing responses to channel blockers, amiloride, and diminazene, while retaining shared properties like inhibition by calcium ions and selective permeability of sodium ions. For example, the acorn worm Schizocardium californicum BASIC displays broad bile acid sensitivity similar to mammals, while the brachiopod Novocrania anomala BASIC is activated solely by ursodeoxycholic acid (UDCA) in our experiments. Mutagenesis of the conserved D444 residue in the pore‐lining region confirms its critical role in gating. Combined functional and phylogenetic analysis suggests BASICs emerged early in bilaterian evolution, evolving from channels that were merely modulated by bile acids, like their acid‐sensing ion channel cousins, into channels that are activated by bile acids. Tissue‐specific expression patterns imply roles in bile acid‐dependent sodium absorption or environmental sensing of bile acid‐like compounds. Given the absence of endogenous bile acids in invertebrates, we propose that invertebrate BASICs may detect environmental compounds, contributing to ecological interactions. This study enhances our understanding of the evolutionary, functional, and ecological roles of BASICs, with implications for future research into their native ligands.

01 Apr 2025·Biophysical Journal

Flipped binding modes for the same agonist in closely related neuropeptide-gated ion channels

Article

Author: Harb, Hassan Y ; Longueville, Léa ; Dandamudi, Mowgli ; Lynagh, Timothy ; Claereboudt, Emily J S

Neuropeptides are inter-cellular signaling molecules occurring throughout animals. Most neuropeptides bind and activate G-protein-coupled receptors, but some also activate ionotropic receptors (or "ligand-gated ion channels"). This is exemplified by the tetra-peptide H-Phe-Met-Arg-Phe-NH₂ (FMRFamide (FMRFa)), which activates mollusk and annelid FMRFa-gated sodium channels (FaNaCs) from the trimeric degenerin/epithelial sodium channel superfamily. Here, we explored the structure-activity relationships determining FMRFa potency at mollusk and annelid FaNaCs in the light of emerging structural data, using synthetic neuropeptide analogs, heterologous expression, and two-electrode voltage clamp. Substitutions of the FMRFa N-terminal phenylalanine residue (F1) and methionine residue (M2) decreased or abolished FMRFa potency at mollusk Aplysia kurodai FaNaC but had little effect at annelid Malacoceros fuliginosus FaNaC1. Conversely, F4 substitutions had little effect on FMRFa potency at A. kurodai FaNaC but either abolished, strongly decreased, or slightly increased potency at M. fuliginosus FaNaC1. Accordingly, recently published high-resolution FaNaC structures show that F1 and F4 residues orient deep into the neuropeptide-binding pockets of A. kurodai FaNaC and M. fuliginosus FaNaC1, respectively. We also use noncanonical amino acid substitutions in A. kurodai FaNaC to describe the physico-chemical determinants of FMRFa F1 binding to A. kurodai FaNaC aromatic side chains. Our results show that the "deeper" of the two FMRFa phenylalanine residues in the binding pocket is crucial for FMRFa potency despite the peptide orienting very differently into the homologous binding sites of two closely related receptors.

01 Jan 2025·Journal of Biological Chemistry

Diarylamidine activation of a brachiopod DEG/ENaC/ASIC channel

Article

Author: Hejnol, Andreas ; Lynagh, Timothy ; Børve, Aina ; Martí-Solans, Josep

Diarylamidines are a group of widely used small molecule drugs. One common use of diarylamidines is their pharmacological inhibition of ligand-gated cation channels, including tetrameric ionotropic glutamate receptors and trimeric degenerin/epithelial sodium channel/acid-sensing ion channels. Here, we discover a degenerin/epithelial sodium channel/acid-sensing ion channel from the brachiopod (lamp shell) Novocrania anomala, at which diarylamidines act as agonists. The channel is closely related to bile acid-gated, pH-gated, and peptide-gated channels but is not activated by such stimuli. We describe activation of the channel by diminazene, 4',6-diamidino-2-phenylindole, and pentamidine, examine several biophysical and pharmacological properties, and briefly explore the molecular determinants of channel activity with site-directed mutagenesis. We term this channel the diarylamidine-activated sodium channel.

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ASIC2

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