This review will focus on an ion channel family that detects changes in extracellular pH: acid-sensing ion channels (ASICs), and more specifically ASIC3. The importance of ion channels is demonstrated by the fact that they account for 19% and 18% of human protein and small drug targets in the ChEMBL database, respectively. The epithelial sodium ion channel/degenerin superfamilyĪpproximately 1.5% of the human genome encodes ion channels (>400 in total), proteins that are integral to cellular excitability in tissues throughout the body. This review will focus on current understanding of ASIC3 function to provide an overview of how ASIC3 contributes to physiology and pathophysiology, examining the mechanisms by which it can be modulated, and highlighting gaps in current understanding and future research directions. Moreover, there is a plethora of evidence using transgenic mouse models and pharmacology, which supports ASIC3 as being a potential target for development of analgesics. Furthermore, certain mediators sensitize ASIC3 enabling smaller proton concentrations to activate it and other mediators can directly activate the channel at neutral pH. ASIC3 can encode prolonged acidosis as a nociceptive signal. ASIC3 is of particular interest, not only because it exhibits high expression in sensory neurones, but also because upon activation it does not fully inactivate: a transient current is followed by a sustained current that persists during a period of extracellular acidity, i.e. ASIC subunits exhibit differential tissue expression and biophysical properties, and the ability of subunits to form homo- and heteromeric trimers further increases the complexity of currents measured and their pharmacological properties. Most ASIC subunits form trimeric ion channels that upon activation by extracellular protons mediate a transient inward current inducing cellular excitability. There are 7 different ASIC subunits encoded by 5 different genes.
Acid-sensing ion channel 3 (ASIC3) belongs to the epithelial sodium channel/degenerin (ENaC/DEG) superfamily.
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