The proton sensitivity, Ca permeability and molecular basis of ASIC channels expressed in glabrous and hairy skin afferents

We contrasted the physiology and peripheral targets of subclassified nociceptive and non-nociceptive afferents that express ASIC-like currents. The threshold for current activation was similar in 8 distinct cell subclasses regardless of functional modality (pH 6.8). When potency was determined from concentration response curves, non-nociceptors exhibited currents with significantly greater potency than all but one class of nociceptors (pH50 = 6.54 and 6.75 vs. 6.20-6.34). In nonnociceptive cells, acid transduction was also confined to a very narrow range (0.1-0.3 vs. 0.8-1.4 pH units for nociceptors). Simultaneous whole cell recording and ratiometric imaging of three peptidergic nociceptive classes was consistent with the expression of Ca permeable ASICs. Sensitivity to psalmotoxin and flurbiprofen indicated the presence of Ca permeable ASIC1a. Immunocytochemistry on these subclassified populations revealed a differential distribution of 5 ASIC proteins consistent with Ca permeability and differential kinetics of proton gated currents (type 5: ASIC1a, 1b, 2a, 2b, 3; type 8a: ASIC1a, 1b, 3; type 8b: ASIC1a, 1b, 2a, 2b, 3). Using DiI tracing, we found that nociceptive classes had discrete peripheral targets. ASIC expressing types 8a and 9 projected to hairy skin, but only type 8a and 13 projected to glabrous skin. Non-ASIC expressing types 2 and 4 were present only in hairy skin. We conclude that ASIC expressing nociceptors differ from ASIC expressing non-nociceptors mainly by range of proton reactivity. ASIC as well as non-ASIC expressing nociceptors have highly distinct cutaneous targets, and only one class was consistent with the existence of a generic C polymodal nociceptor (type 8a). ASIC and Nociceptors JN-00861-2005.R2 3