Acid-sensing ion channels in sensory perception

Acid-activated currents blocked by amiloride have been reported for a long time in most neurons of the mammalian brain as well as in sensory neurons (1). A decade ago, Waldmann and colleagues (2) were the first to clone the ion channels underlying these currents, which have been called acid-sensing ion channels (ASICs).2 ASICs are neuronal voltage-insensitive cationic channels activated by extracellular protons. They belong to the ENaC/DEG (epithelial amiloride-sensitive Na+ channel and degenerin) family of ion channels (3). ASICs share the same overall structure with other members of this family, which is characterized by two hydrophobic transmembrane regions flanking a large extracellular domain representing more than 50% of the protein and comprising many conserved cysteines (Fig. 1). Functional ASICs probably assemble as tetramers, as proposed for two other channels of the ENaC/DEG family, i.e. ENaC and FaNaC (the invertebrate FMRF-amide-activated Na+ channel). The ASIC family in mammals (ASICs have also been cloned from toadfish, lamprey, shark, and zebrafish) comprises four different genes encoding seven isoforms (4, 5) (Fig. 1). ASICs are widely expressed in neurons of both the central and the peripheral nervous system but have also been detected in non-neuronal tissues including testis (human ASIC3), pituitary gland (ASIC4), lung epithelial cells (ASIC3), and bone (ASIC1-3) (Table 1).