Zn2+ and H+ are coactivators of acid-sensing ion channels

Acid-sensing ion channels (ASICs) are cationic channels activated by extrac ellular protons. They are expressed in sensory neurons, where they are thou ght to be involved in pain perception associated with tissue acidosis. They are also expressed in brain. A number of brain regions, like the hippocamp us, contain large amounts of chelatable vesicular Zn2+. This paper shows th at Zn2+ potentiates the acid activation of homomeric and heteromeric ASIC2a -containing channels (i.e. ASIC2a, ASIC1a+2a, ASIC2a+3), but not of homomer ic ASIC1a and ASIC3. The EC50 for Zn2+ potentiation is 120 and 111 muM for the ASIC2a. and ASIC1a+2a current, respectively. Zn2+ shifts the pH depende nce of activation of the ASlCIa+2a current from a pH(0.5) of 5.5 to 6.0. Sy stematic mutagenesis of the 10 extracellular histidines of ASIC2a leads to the identification of two residues (His-162 and His-339) that are essential for the Zn2+ potentiating effect. Mutation of another histidine residue, H is-72, abolishes the pH sensitivity of ASIC2a. This residue, which is locat ed just after the first transmembrane domain, seems to be an essential comp onent of the extracellular pH sensor of ASIC2a.