Acid-Sensing Ion Channel Physiology and Pharmacology

Acid-sensing ion channels (ASICs) are proton-gated cation channels belonging to the degenerin/epithelial sodium channel superfamily that detect extracellular acidification across a variety of tissues. Composed of multiple subunits that assemble into homomeric and heteromeric complexes, ASICs open in response to decreases in extracellular pH, permitting Na+ influx that initiates rapid neuronal and non-neuronal signalling. ASICs are widely expressed in the central and peripheral nervous systems where they contribute to pain sensation, mechanotransduction, learning and memory, and neuroinflammatory processes. Their roles in pathophysiological conditions—such as ischaemic stroke, chronic pain and tumour acidosis—have made them attractive targets for therapeutic modulation. Pharmacological agents range from small-molecule inhibitors and peptidic toxins to endogenous lipids and synthetic allosteric modulators, each offering distinct mechanisms to fine-tune channel gating, desensitisation kinetics and ion selectivity. Ongoing structural and functional studies continue to reveal the molecular basis of proton sensing and drug interaction, paving the way for targeted interventions in acid-related disorders.

Research from Nature Portfolio

Recent studies have demonstrated that glutamate acts as a positive allosteric modulator of ASIC1a, increasing proton affinity and channel open probability to aggravate neurotoxicity in ischaemic stroke models. Structure-based mapping identified a discrete glutamate-binding cavity in the extracellular domain of ASIC1a, enabling the design of a novel small molecule that selectively blocks this site without affecting N-methyl-D-aspartate receptors, thereby reducing infarct volume and improving functional recovery. In parallel, cryo-electron microscopy analyses of neuropeptide-gated DEG/ENaC channels have unveiled ligand-induced conformational changes that mirror proton-gated ASIC activation, offering a structural framework to understand gating mechanisms across the family. Insights from these high-resolution structures inform the rational development of selective ASIC modulators with therapeutic potential.

Acid-Sensing Ion Channel Physiology and Pharmacology publication trend

The graph below shows the total number of articles in acid-sensing ion channel physiology and pharmacology across all publications each year (not limited to Nature Index journals).

Technical terms

Acid-sensing ion channel (ASIC): Proton-gated cation channel in the degenerin/ENaC superfamily mediating rapid Na+ influx in response to extracellular acidification.

Allosteric modulation: Regulation of channel gating by ligands binding to sites distinct from the ion-conducting pore.

Neural progenitor cell (NPC): Precursor cell capable of migrating, proliferating and differentiating into neurons and glia.

Necroptosis: Programmed necrotic cell death driven by kinase signalling pathways, distinct from apoptosis.

Penumbra: Tissue region surrounding an ischaemic core that remains at risk but salvageable through therapeutic intervention.

References

1. Glutamate acts on acid-sensing ion channels to worsen ischaemic brain injury. Nature (2024).
2. Targeting ASIC1a Promotes Neural Progenitor Cell Migration and Neurogenesis in Ischemic Stroke. Research (2023).
3. Structural basis for excitatory neuropeptide signaling. Nature Structural & Molecular Biology (2024).
4. Isolation of a Tarantula Toxin Specific for a Class of Proton-gated Na+ Channels*. Journal of Biological Chemistry (2000).
5. Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conduction. eLife (2015).