Acid sensing ion channels (ASICs) in muscle skeletal afferents are heteromultimers with ASIC3 being a necessary component

Abstract

ASICs are activated by extracellular acidosis, and in skeletal muscle afferents are thought to sense metabolic changes associated with ischemia and exercise. ASICs are formed as homo‐ or heterotrimers of several isoforms: ASIC1a, ‐1b, ‐2a, ‐2b, and ‐3, with each channel displaying distinct biophysical and pharmacological properties. To dissect the ASIC composition in muscle afferents, we studied the properties of pH‐evoked currents (amplitude, pH sensitivity, the kinetics of desensitization and recovery from desensitization, and pharmacological modulation) in isolated mouse skeletal muscle afferents that had been labeled using a retrograde tracer dye (DiI) injected into the gastrocnemius muscle from C57Bl6 (WT) and ASIC null mice using whole‐cell patch‐clamp. We found ASIC‐like currents in 60–70% of WT muscle afferents, and their fast kinetics of desensitization indicate that they are carried by heteromeric ASIC channels, with ASIC3 being a required component. Currents from ASIC1a −/− muscle sensory neurons were less pH sensitive and displayed faster recovery; those from ASIC2 −/− mice showed diminished potentiation by zinc; and currents ASIC3 −/− mice displayed markedly slower desensitization kinetics than those from WT mice. Finally, ASIC‐like currents were absent from triple null mice lacking ASIC1a, ‐2, and ‐3. We conclude ASICs in skeletal muscle afferents are heteromers of multiple subunits.