Modulatory action of RFamide-related peptides on acid-sensing ionic channels is pH dependent: the role of arginine

Acid-sensing ionic channels (ASICs) are involved in such functions of the sensory nervous system as mechanoreception, nociception and perception of acid taste. Phe-Met-Arg-Phe amide-related (FMRFa-related) peptides in micro m concentrations slow down the rate of ASICs desensitization. Here we report that this effect is strongly pH dependent: the lower the pH used to activate ASICs, the larger is the modulatory effect of Arg-Phe amide-related (RFa-related) peptides. Pre-application of the peptides results in a change to the desensitization kinetics of the ASICs-operated current from monoexponential to biexponential: the fast component retains the control kinetics, whereas the slow one is induced by the peptide. The lower the pH, the larger is the slow component, whereas there is practically no modulation at pH 6.6. Phe-Met-Val-Phe amide (FMVFa), which has neutral valine instead of arginine, similarly modulates the kinetics of ASICs, but does not reveal pH dependence of this action. Thus, positively charged arginine regulates the access of the RFa-related peptides to the modulatory site. We suggest that the pH dependence of the modulatory action of RFa-related peptides can be associated with the interaction of a positively charged arginine with histidine residues in the molecule of ASIC.