P2X3 receptor gating near normal body temperature

Abstract

P2X3 purinoreceptors expressed in mammalian sensory neurons are involved in nociception, mechanosensory transduction, and temperature sensation. Homomeric P2X3 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 P2X3 receptors is abnormal: development of desensitization does not depend on temperature within the range between 25 and 40 degrees C, whereas the recovery from desensitization is greatly \accelerated with temperature increase (Q10 approximately 10). The sensitivity of HABS to low nanomolar ATP near normal body temperature (35 degrees C) is substantially lower than at 25 degrees C (IC50 is 3.2+/-0.3 nM at 35 degrees C and 0.79+/-0.09 nM at 25 degrees C). HABS itself is subjected to slow desensitization partially loosing its sensitivity to ATP: at 35 degrees C 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 P2X3 receptors may be related to their pivotal role in the processing of thermal sensitivity as revealed by recent knockout experiments.

Activation of P2X7 receptors in glial satellite cells reduces pain through downregulation of P2X3 receptors in nociceptive neurons

“…The kinetic properties of P2X3R-mediated currents are unusual. Although the development of desensitization of P2X3Rs is independent of temperature and external ATP concentrations, the recovery from desensitization is highly temperature-dependent (36) and sensitive to use-dependent inhibition of nanomolar ATP (36,37). P2X3R-mediated currents are therefore likely to recover rather quickly from desensitization near body temperature, thus allowing the receptor to be repetitively activated.…”

Activation and Regulation of Purinergic P2X Receptor Channels

“…Table 3 summarizes the pharmacological profile of homomeric P2X3Rs. ATP is a full agonist for rP2X3R with estimated EC 50 values of 1.2 M (Chen et al, 1995), 2.6 M (Pratt et al, 2005), 4.1 M (Asatryan et al, 2008), and 7.3 M (Grote et al, 2005), but the precision of these estimates is limited by profound desensitization (Khmyz et al, 2008). Similar to the rP2X1R, ␣␤-meATP is a full agonist at rP2X3R, acting with a potency similar to (Pratt et al, 2005;Asatryan et al, 2008) or slightly lower than (Chen et al, 1995) that of ATP.…”

The Purinergic System and Glial Cells: Emerging Costars in Nociception

“…P2X receptors are differentially distributed among the cell types in different brain areas. Peripheral neurons mainly express the P2X3 and P2X2/3 receptor subtypes, which are involved in pain and temperature perception (see below) [19]. All P2X receptor subtypes can modulate membrane action potential.…”