Abstract
Acid-sensing ion channels (ASICs) are proton-gated cation channels that detect and signal increases in proton concentration. ASIC1a and ASIC3 play a role in pain sensation associated with extracellular acidification. There are few selective modulators of ASIC3, including the tetrapeptide RFamide RPRFa, which slows the acute desensitization of ASIC3. Here we describe the peptide WRPRFa as the most potent ASIC3 activator to date and a more effective pharmacological tool. WRPRFa enhances the pH sensitivity of ASIC3 and effectively removes acute desensitization. Additionally, we demonstrate that ASIC3 can undergo tachyphylaxis at very acidic pH, which is accelerated by WRPRFa. Our work characterizes a selective and effective in vitro tool to study the interaction of RFamides and ASICs, and by extension gating mechanisms of ASIC3.