On a broad scale, ASICs are potential drug targets due to their involvement in pathological states such as retinal damage, seizures, and ischemic brain injury.
[4][5] Each acid-sensing ion channel is composed of a 500-560 amino acid sequence, which is constructed into a six transmembrane segment—two per subunit (TMD1 and TMD2), a cytoplasmic amino-carboxyl termini, and a large extracellular domain.
The central tunnel runs directly between the trimeric unit, where it has large constricted areas that change in size and shape depending on channel state.
TMD2 is primarily involved with lining of the lumen within the pore and inactivation gate of the channel, where as TMD1 holds the protein within the cell's lipid bilayer.
[3] In-between the TMD2 segments resides a selectivity filter that forms the narrowest part of the pore, which is responsible for ASIC permissibility to mostly Na+.
Nicknamed the "GAS belt", all three carbonyl oxygens line the pore, producing a negative potential that contributes to the conductance of cations.
[3] The specific amino acid residue of aspartate on the extracellular side lumen of TMD2 in ASIC1 has been linked to the channel's low Ca2+ conductance.
[3] These residues form an acidic pocket that express electrostatic potentials that are responsible for pH-dependency in channel activation and modulation.
Glycosylation is also apparent within the extracellular region, playing an important role in the trafficking the channel to the membrane's surface as well as establishing the ASIC's sensitivity to pH levels.
Further experimental evidence has indicated that Ca2+ may also play a pivotal role in modulating proton affinity of ASIC gating both within the pore and on the extracellular domain.
In the peripheral nervous system, ASICs are located within the cell bodies of postsynaptic membranes and sensory nerve terminals.
Additionally, ASICs are typically found in afferent nerve fibers of the skin, muscles, joints, and viscera, where they have been discovered to be associated with pain, taste, and gastrointestinal functions.
[8] ASIC1a channels specifically open in response to pH 5.0-6.9 and contribute to the pathology of ischemic brain injury because their activation causes a small increase in Ca2+permeability and an inward flow of Ca2+.
[10] The effects of both ASIC and NMDA blockades have been studied to determine the roles of both channels in Ca2+ toxicity and assess their respective contributions.
[10] Due to the role of acid sensing ion channels in pain perception and several pathophysiological processes, they have a pharmacological significance as a drug target for inhibition.
Modulation of ASIC activity may additionally control the adverse behavioral and emotional symptoms of chronic pain such as anxiety and depression.
Activation of the channel causes increased permeability of sodium ions which depolarizes the cell and induces the firing of an action potential.
During a migraine, cortical spreading depression is observed which causes ion imbalances and the release of charged molecules which may activate ASIC.
[11][10] A small molecule inhibitor, A-317567, shows more therapeutic potential than amiloride with a higher specificity to ASIC channels and increased potency.
[13] Hi1a is a peptide from the venom Hadronyche infensa (the K’gari funnel web spider) which inhibits ASIC1a and has been used in rodent models to reduce myocardial ischemia.
[14] Commonly used non-steroid anti-inflammatory drugs (NSAIDs) have been found to play a role in ASIC inhibition which contributes to pain modulation.
[10] By furthering research on the pharmacological potential in ASIC inhibition, patients suffering with chronic pain and various pathologies associated with acidosis may have greater treatment options in the future.