Experimental and modeling studies of desensitization of P2X3 receptors.

Molecular Pharmacology
Elena SokolovaRashid Giniatullin

Abstract

The function of ATP-activated P2X3 receptors involved in pain sensation is modulated by desensitization, a phenomenon poorly understood. The present study used patch-clamp recording from cultured rat or mouse sensory neurons and kinetic modeling to clarify the properties of P2X3 receptor desensitization. Two types of desensitization were observed, a fast process (t1/2 = 50 ms; 10 microM ATP) following the inward current evoked by micromolar agonist concentrations, and a slow process (t1/2 = 35 s; 10 nM ATP) that inhibited receptors without activating them. We termed the latter high-affinity desensitization (HAD). Recovery from fast desensitization or HAD was slow and agonist-dependent. When comparing several agonists, there was analogous ranking order for agonist potency, rate of desensitization and HAD effectiveness, with 2-methylthioadenosine triphosphate the strongest and beta,gamma-methylene-ATP the weakest. HAD was less developed with recombinant (ATP IC50 = 390 nM) than native P2X3 receptors (IC50 = 2.3 nM). HAD could also be induced by nanomolar ATP when receptors seemed to be nondesensitized, indicating that resting receptors could express high-affinity binding sites. Desensitization properties were well accounted for b...Continue Reading

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Citations

Apr 12, 2008·Purinergic Signalling·Fritz Markwardt
Dec 14, 2011·Purinergic Signalling·Lucio Apicella, Elsa Fabbretti
May 22, 2013·European Journal of Medicinal Chemistry·Catia LambertucciRosaria Volpini
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Sep 15, 2009·PloS One·Sang Ok Song, Jeffrey Varner
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Sep 5, 2008·Neuropharmacology·Alexander GroteRonald Jabs
Apr 23, 2013·Journal of Neurochemistry·Aswini GnanasekaranElsa Fabbretti
Mar 2, 2012·The Journal of Biological Chemistry·Ralf HausmannPeter Illes
Apr 14, 2017·The Journal of Pharmacology and Experimental Therapeutics·Yevheniia IshchenkoRashid Giniatullin
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Dec 26, 2008·Molecular Pain·Yoshizo MatsukaIgor Spigelman
Apr 1, 2016·Molecular Pain·Viacheslav Viatchenko-KarpinskiNatalia Lozovaya
Sep 25, 2007·The Journal of Biological Chemistry·Zoltan GerevichPeter Illes
Jul 18, 2009·Journal of Medicinal Chemistry·Rosaria VolpiniGloria Cristalli
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