ASIC3 | acid-sensing Ion Channel 3
Acid-sensing ion channels, member of the ENaC/Degenerin superfamily
Members and topology:
The channels are encoded by five genes: ASIC1 - ASIC5. ASIC1a, ASIC1b, ASIC2a, ASIC2b are splice variants. Each subunit has 2 transmembrane domains flanking a large extracellular loop with short intracellular N and C termini. Three of these protein subunits assemble to form the ASIC ion channel, which can combine into both homotrimeric and heterotrimeric channels.
Regulation and function:
Neuronal voltage-insensitive cationic channels activated by extracellular protons. ASICs are Na+ permeable with ASIC1a showing low Ca2+ permeability. The role of the ASIC is to sense reduced levels of extracellular pH and result in a response or signal from the neuron.
ASIC3: Background information
Acid-sensing ion channel 3 (ASIC3) is also known as amiloride-sensitive cation channel 3 (ACCN3) or testis sodium channel 1 (TNaC1). ASIC3 is a cation channel with high affinity for sodium, which is gated by extracellular protons and inhibited by the diuretic amiloride. In sensory neurons, ASIC3 is proposed to mediate the pain induced by acidosis that occurs in ischemic, damaged or inflamed tissue. The channel generates a biphasic current with a fast inactivating and a slow sustained phase.
Primarily expressed in central and peripheral neurons including nociceptors where they participate in neuronal sensitivity to acidosis. Also present in taste receptor cells, photoreceptors and retinal cells, testis, lung epithelial cells, urothelial cells, adipose cells, vascular smooth muscle cells, immune cells and bone.
Somatic and visceral nociception, inflammatory pain
Ischaemic stroke, implicated in multiple sclerosis, Huntington’s disease, Parkinson’s disease and spinal cord injury
Homotrimer or heterotrimer with other ASIC proteins (ASIC2, ASIC4).
STOM (Erythrocyte band 7 integral membrane protein) regulates channel activity. DLG4 (Disks large homolog 4) may reduce the amplitude of ASIC3 acid-evoked currents by retaining the channel intracellularly. LIN7B (Protein lin-7 homolog B) may increase the amplitude of ASIC3 acid-evoked currents by stabilizing the channel at the cell surface. MAGI1 (Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1) may regulate acid-induced ASIC3 currents by modulating its expression at the cell surface. Interacts furthermore with GOPC (Golgi-associated PDZ and coiled-coil motif-containing protein) which may regulate currents by modulating cell surface expression.
Inhibitors: Amiloride, nafamostat mesilate, A-317567, APETx2, aspirin. Potentiators: FMRFa, MitTx
Patch Clamp: whole cell, room temperature, pH activation
Reviews and Links
- Lingueglia E. & Lazdunski M., Pharmacology of ASIC channels (2013) Wiley Interdisciplinary Reviews: Membrane Transport and Signaling 2:155–171. doi: 10.1002/wmts.88
- Deval E. et al., Acid-sensing ion channels (ASICs): pharmacology and implication in pain. (2010) Pharmacology & Therapeutics 128:549–558
- Wemmie J.A. et al., Acid-sensing ion channels in pain and disease. (2013) Nature Reviews Neuroscience 14(7):461-471. doi: 10.1038/nrn3529
Transporter classification database: