title: Potent desensitization of human P2X3 receptors by diadenosine polyphosphates.
abstract: In this study, the receptor desensitizing effects of diadenosine polyphosphates at recombinant human P2X3 (hP2X3) receptors were examined. Administration of Ap3A, Ap4A, Ap5A or Ap6A inhibited the hP2X3 receptor-mediated response to a subsequent application of 3 muM alphabeta-methyleneATP (alphabeta-meATP), in a concentration-dependent manner, with IC50 values 2707, 42, 59 and 46 nM, respectively. These agonists did not desensitize alphabeta-meATP responses mediated by the slowly desensitizing heteromeric human P2X2/3 receptor. hP2X3 receptor desensitization was reversible and was not observed following the increase in intracellular Ca2+ levels produced by carbachol. A similar pattern of desensitization evoked by Ap5A was also observed using electrophysiological recordings of Xenopus oocytes expressing hP2X3 receptors. These data demonstrate that diadenosine polyphosphates, found endogenously in the central nervous system, can readily desensitize hP2X3 receptors at nanomolar concentrations that are 10-fold lower than are required to produce agonist-induced receptor activation. Thus, P2X3 receptor desensitization by diadenosine polyphosphates may provide an important modulatory mechanism of P2X3 receptor activation in vivo.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, R04PM, AP9A/218, 100 Abbott Park Road, Abbott Park, IL 60064-6123, USA.
authors.forename: Heath A
authors.initials: HA
authors.lastname: McDonald
authors.forename: Katharine L
authors.initials: KL
authors.lastname: Chu
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Bianchi
authors.forename: David G
authors.initials: DG
authors.lastname: McKenna
authors.forename: Clark A
authors.initials: CA
authors.lastname: Briggs
authors.forename: Edward C
authors.initials: EC
authors.lastname: Burgard
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Lynch
authors.forename: Connie
authors.initials: C
authors.lastname: Faltynek
authors.forename: Jayne
authors.initials: J
authors.lastname: Cartmell
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jarvis
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D015226:Dinucleoside Phosphates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006801:Humans; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D058477:Receptors, Purinergic P2X3; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D018679:Cholinergic Agonists; D015226:Dinucleoside Phosphates; C546407:P2RX3 protein, human; D018048:Receptors, Purinergic P2; D058477:Receptors, Purinergic P2X3; D011994:Recombinant Proteins; C012275:P(1),P(5)-di(adenosine-5'-)pentaphosphate; C020733:diadenosine tetraphosphate; C011440:diadenosine triphosphate; D000255:Adenosine Triphosphate; D002217:Carbachol