Recent studies demonstrated modulatory effects of low [ATP] on P2X3 receptors including receptor current enhancement (J.Nsci. 05, 25:7734) and a use-dependent receptor inhibition (J.NSci. 05, 25:7359). However, so far there is no information available about the influence of low [agonist] on the receptor gating kinetics. To address this issue, we studied the effect of ambient nanomolar [ATP] on P2X3 receptor activation and desensitization. First, we asked whether persistent ATP affects the receptor current decay. Therefor, P2X3 mediated currents, elicited by pressure application of saturating [ATP], were analyzed after 4 minutes pre-application of low [ATP]. Second, we employed UV-flash photolysis of caged ATP to investigate whether low [ATP] affects the current activation. We found that persistent low [ATP] caused a pronounced deceleration of current activation and decay. This priming effect of nanomolar [ATP] on the kinetics of P2X3 receptor gating indicates a mechanism different from use-dependent receptor inhibition. We suggest an extended dynamic model, including an additional desensitization state. Our data are in line with the hypothesis that P2X3 receptors bear a high affinity binding site already in the resting state. They are masked by fast receptor desensitization, as described already for P2X1 receptors (J.Biol.Chem. 04, 279:6426).

The slow down of P2X3 gating can be considered as an additional mechanism for fine tuning of the nociceptive system, driven by the actual endogenous agonist concentration. (Supported by DFG)