TY - JOUR T1 - Naked mole-rat acid-sensing ion channel 3 forms non-functional homomers, but functional heteromers JF - bioRxiv DO - 10.1101/166272 SP - 166272 AU - Laura-Nadine Schuhmacher AU - Shyam Srivats AU - Gerard Callejo AU - Ewan St. John Smith Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/07/22/166272.abstract N2 - Acid-sensing ion channels (ASICs) form both homotrimeric and heterotrimeric ion channels that are activated by extracellular protons and are involved in a wide range of physiological and pathophysiological processes, including pain and anxiety. The ASIC3 subunit has been shown to be of particular importance in the peripheral nervous system with pharmacological and genetic manipulations demonstrating a role in pain. Naked mole-rats are insensitive to acid as a noxious stimulus and show diminished avoidance to acidic fumes, ammonia and carbon dioxide. Here we clone naked mole-rat ASIC3 (nmrASIC3) and demonstrate that although it traffics to the plasma membrane it is insensitive to protons. However, in line with previous demonstration of ASIC3 mRNA expression in dorsal root ganglia (DRG) neurons, we demonstrate that the ASIC3 antagonist APETx2 reversibly inhibits ASIC-like currents in naked mole-rat DRG neurons. We further show that like the proton-insensitive ASIC2b and ASIC4, nmrASIC3 forms functional heteromers with other ASIC subunits. An amino acid alignment of ASIC3s identified sequence differences that might underlie the proton-insensitivity of nmrASIC3, however, mutating rat ASIC3 (rASIC3) in line with these differences only produced minor differences in channel function and replacing nmrASIC3 sequence with that of rASIC3 did not produce a proton-sensitive ion channel. ER -