Acid-sensing ion channels: structure, function, pharmacology, and clinical significance

Changes in local proton concentrations within the body occur during synaptic transmission and metabolic activity and along the digestive tract. Perturbations to the strictly controlled physiological tissue pH are often associated with pathological processes. As such, many cell types require the ability to sense and respond to changes in local proton concentrations. Acid-sensing ion channels (ASICs) have been identified in all groups of Bilateria except for nematodes, arthropods, and mollusks. They are part of the epithelial Na⁺ channel/degenerin (ENaC/DEG) family, which encompasses ion channels across a wide range of tissues and organisms. ENaC/DEG channels are constitutively active or can be activated by various stimuli, such as mechanical stimuli or the binding of peptides or protons. ASICs are low pH-activated Na⁺-selective channels, formed by the assembly of three identical or homologous subunits around a central pore. In mammals, ASICs are mostly expressed in the nervous system. Extensive structure-function studies have identified residues involved in ion permeation and in the control and modulation of ASIC activity. The biological functions of ASICs are associated with situations of lowered pH, such as high neuronal activity, ischemia, and inflammation. Experiments with rodents showed roles of ASICs in the expression of fear, learning, pain sensation, and neurodegeneration. This review comprehensively examines ASICs, covering their evolutionary origins, biophysical properties, structure-function relationships, physiological and pathological roles, and their regulation and pharmacology.