Desensitization, recovery and Ca2+-dependent modulation of ATP-gated P2X receptors in nociceptors

We have shown the presence and activity of ATP-gated ion channels (P2X receptors) in nociceptive nerve endings, supporting the theory that these channels mediate some forms of nociception [Cook S. P., Vulchanova L., Hargreaves K. M., Elde R. and McCleskey E. W. (1997) Distinct ATP receptors on pain-sensing and stretch-sensing neurons. Nature 387, 505-508]. The kinetics and pharmacology of ATP-gated currents in nociceptors suggest that the channels are comprised of either homomeric or heteromeric combinations of P2X3 receptors. Consistent with the diverse nature of P2X structure, electrophysiological responses of rat tooth-pulp nociceptors fall into two distinct classes based on desensitization and recovery kinetics. Here, we quantified the dramatic differences in desensitization kinetics of transient and persistent currents. The major component of transient P2X current desensitized with a tau(decay) = 32 +/- 2 msec, while persistent current desensitized >100-fold more slowly, tau(decay) = 4000 +/- 320 msec, Both currents recovered from desensitization in minutes: tau(recovery) = 4 min for transient current, and tau(decay) = 0.7 +/- 0.2 min for persistent current. Persistent current recovery was often accompanied by a current ''overrecovery'' that averaged ca threefold magnitude prior to desensitization. Comparison of ATP current in elevated Ca-ext(2+) also revealed differences in transient and persistent currents. In 2 mM Ca-ext(2+) medium, decrease of Na-ext(+) resulted in an almost complete reduction of persistent, but not transient, current. Subsequent elevation of Ca-ext(2+) greatly increased the transient, but not persistent, current. Mechanistic explanations for either the increase in transient current magnitude by elevated Ca-ext(2+), or persistent current overrecovery may reflect endogenous pathways for P2X receptor modulation. (C) 1997 Elsevier Science Ltd.