P2X3 receptor gating near normal body temperature

P2X(3) purinoreceptors expressed in mammalian sensory neurons are involved in nociception, mechanosensory transduction, and temperature sensation. Homomeric P2X(3) receptors desensitize rapidly (< 500 ms after activation by an agonist) and recover from desensitization very slowly (20-25 min at room temperature). They are susceptible to use-dependent inhibition by low nanomolar concentrations of ATP through developing the "high-affinity binding site" (HABS), which traps ATP molecules, thus keeping receptors in a desensitized state (Pratt et al., J Neurosci 25:7359-7365, 2005). Indeed, here we demonstrated directly that the desensitization of the receptor, after being activated by ATP, proceeds independently of the presence of agonist. We found that the temperature sensitivity of P2X(3) receptors is abnormal: development of desensitization does not depend on temperature within the range between 25 and 40C, whereas the recovery from desensitization is greatly\accelerated with temperature increase (Q (10) similar to 10). The sensitivity of HABS to low nanomolar ATP near normal body temperature (35C) is substantially lower than at 25C (IC50 is 3.2 +/- 0.3 nM at 35C and 0.79 +/- 0.09 nM at 25C). HABS itself is subjected to slow desensitization partially loosing its sensitivity to ATP: at 35C the response completely recovers in 10 min in the presence of 3 nM ATP, making the receptor operational in the presence of up to 30 nM ATP. Unusual combination of temperature sensitivity/insensitivity of P2X(3) receptors may be related to their pivotal role in the processing of thermal sensitivity as revealed by recent knockout experiments.