Acid-sensing ion channel

Acid-sensing ion channels (ASICs) are neuronal voltage-insensitive sodium channels activated by extracellular protons permeable to Na+. ASIC1 also shows low Ca2+ permeability. ASIC proteins are a subfamily of the ENaC/Deg superfamily of ion channels. These genes have splice variants that encode for several isoforms that are marked by a suffix. In mammals, acid-sensing ion channels (ASIC) are encoded by five genes that produce ASIC protein subunits: ASIC1, ASIC2, ASIC3, ASIC4, and ASIC5. Three of these protein subunits assemble to form the ASIC, which can combine into both homotrimeric and heterotrimeric channels typically found in both the central nervous system and peripheral nervous system. However, the most common ASICs are ASIC1a and ASIC1a/2a and ASIC3. ASIC2b is non-functional on its own but modulates channel activity when participating in heteromultimers and ASIC4 has no known function. 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. Acid-sensing ion channels (ASICs) are neuronal voltage-insensitive sodium channels activated by extracellular protons permeable to Na+. ASIC1 also shows low Ca2+ permeability. ASIC proteins are a subfamily of the ENaC/Deg superfamily of ion channels. These genes have splice variants that encode for several isoforms that are marked by a suffix. In mammals, acid-sensing ion channels (ASIC) are encoded by five genes that produce ASIC protein subunits: ASIC1, ASIC2, ASIC3, ASIC4, and ASIC5. Three of these protein subunits assemble to form the ASIC, which can combine into both homotrimeric and heterotrimeric channels typically found in both the central nervous system and peripheral nervous system. However, the most common ASICs are ASIC1a and ASIC1a/2a and ASIC3. ASIC2b is non-functional on its own but modulates channel activity when participating in heteromultimers and ASIC4 has no known function. 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. 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 intracellular amino-carboxyl termini domains are vital to the channel's intracellular protein interactions and modulations, ion permeability, and gating. However, the gating and mechanics of each acid-sensing ion channel is determined by the combination of ASIC subunits that form its structure. The mechanics of the pore function is fundamental to the channel's structure. Between the three ASIC1 subunits, a tunnel extends from the top of the extracellular domains to the cytoplasm of the cell. 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. The two transmembrane domains (TMD1 and TMD2) of each of the three ASIC subunits are responsible for the channel's pore. 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. TMD1 is connected to the β-sheets of the extracellular domain that flex to widen the extracellular domain to allow for ion passage through the channel. 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+. For ASIC1, nine amino acid residues, three contributed by each ASIC subunit (Gly443, Ala444, Ser445), form the selectivity filter. Nicknamed the 'GAS belt', all three carbonyl oxygens line the pore, producing a negative potential that contributes to the conductance of cations. 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. Additionally, The n-termini residues of the transmembrane region has also shown selectivity for Na+, since mutations within this region has altered function and of Na+ conductance. ASIC's have a large, fist-like extracellular region that consumes most of the proteins structure. Within its 'fist-like' structure there is a wrist, palm, finger, knuckle, thumb and β-ball domains. The 'palm' makes up most of the extracellular domain, formed by seven β-sheets, where as the rest of the secondary structural domains are composed of α-helical segments. Distinguished by its specific amino acid configurations, the extracellular region is fundamental to the induction of activation/inactivation along with pH gating. The specific β-sheet loop area between the 'palm' and 'thumb' domains has shown involvement in the signal transduction from the extracellular domain to the transmembrane regions, resulting in a conformational change of the ASIC to its open state. However, it remains fairly inconclusive of which particular residues interact with protons to activate the channel. In 2009, studies may have established a relationship between the aromatic residues Tyr72, Pro287, and Trp288 and proton-gating of the ASIC. These residues form an acidic pocket that express electrostatic potentials that are responsible for pH-dependency in channel activation and modulation. This pocket in the extracellular domain acts as a reserve for cations to concentrate to further assist in Na+ influx. 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. The role of the ASIC is to sense reduced levels of extracellular pH and result in a response or signal from the neuron. The ligand that binds to the activation site has long been thought to be exclusively protons; however, recent studies have shown that ASIC4 and ASIC1 can be activated at normal pH levels, indicating other types of ligand binders. Under increased acidic conditions, a proton binds to the channel in the extracellular region, activating the ion channel to go through conformational change therefore opening transmembrane domain 2 (TMD2). This results in the influx of sodium ions through the lumen of TMD2. All ASICs are specifically permeable to sodium ions. The only variant is ASIC1a which also has a low permeability to calcium ions. The influx of these cations results in membrane depolarization. Voltage-gated Ca2+ channels are activated resulting in an influx of calcium into the cell. This causes depolarization of the neuron and an excitatory response released. In ASIC1a, Ca2+ increase inside the cell is a result of calcium influx directly through the channel. Once activated the ASIC can go on to trigger multitudes of different effector proteins and signaling molecules to result in different reactions from the cell. Namely, α-Actinin results in heightened pH sensitivity and desensitization recovery. They can also increase current flow density through the channel. There are also many protein kinases that regulate ASIC function through phosphorylation. These include protein kinase A (PKA) and protein kinase C (PKC). There are thought to be many more regulators, yet their effects have not been experimentally concluded. There are some other factors that can play a role on the regulation of the ASICs. The presence of matured N-linked glycans on the surface of the channel is said to allow the channel to preferentially traffic for ASIC1a. This is a result from the increased N-glycosylation sites on ASIC1a and ASIC2a. The high levels of glycerol (known to expedite protein maturation) on ASIC2 surface also aids in the implication that regulation of these channels' function is reliant on protein maturation. It is also hypothesized that oxidation plays a role in trafficking.