Liu, Min; (2001) Coexpression of recombinant P2X receptors and their relation to ATP-gated channels in sensory neurons. Doctoral thesis (Ph.D.), University College London.

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Abstract

Recombinant P2X receptors expressed in Xenopus oocytes, which reflect the properties of ATP-gated channels in sensory neurons, were studied individually, or expressed together, or coexpressed with VR1 receptors. Coexpression of P2X2 and P2X3 subunits gave rise to three populations of receptors: homomeric P2X2 and P2X3 receptors, and heteromeric P2X2/3 receptors, the proportions of which were changed by altering the ratios of P2X2 and P2X3 cRNA injected. The pharmacological characteristics of ATP responses evoked by this complement of P2X receptors bore a close similarity to the range of ATP responses evoked in sensory neurons. Agonist and antagonist profiles of P2X2/3 receptors were closer to those of P2X3 receptors yet showed the desensitization kinetics and sensitivity to extracellular pH and Zn2+ of P2X2 receptors. Activation of P2X3 receptors neither enhanced nor diminished the activation of VR1 receptors, both of which occur on nociceptors. In contrast, the activation of VR1 receptors inhibited the activation of P2X3 receptors, but only when ATP was applied during the peak of capsaicin-activated currents. The degree of one-way modulation was dependent on the degree of activation of VR1 receptors. Capsaicin responses, but not ATP responses, were altered to the same extent by extracellular pH as when these receptors were expressed alone. This one-way modulation of P2X3 receptors by the activation of VR1 receptors may influence nociceptive transmission in sensory neurons. Diinosine pentaphosphate (Ip5I) exhibited selectivity for P2X1 receptors over P2X3 receptors, but otherwise failed to inhibit ATP responses at P2X2, P2X4 and P2X2/3 receptors. The selective inhibition by Ip5I for P2X3 over P2X2/3 receptors provided a useful pharmacological tool to study the composition of P2X subunits in sensory neurons. This novel P2X antagonist might fill a long-term need for highly potent and selective antagonists to study P2X receptors and nociception in sensory neurons.

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