TY - JOUR T1 - Sensitization by Extracellular Ca<sup>2+</sup> of Rat P2X<sub>5</sub> Receptor and Its Pharmacological Properties Compared with Rat P2X<sub>1</sub>. JF - Molecular Pharmacology JO - Mol Pharmacol SP - 957 LP - 966 DO - 10.1124/mol.62.4.957 VL - 62 IS - 4 AU - Scott S. Wildman AU - Sean G. Brown AU - Mary Rahman AU - Carole A. Noel AU - Linda Churchill AU - Geoffrey Burnstock AU - Robert J. Unwin AU - Brian F. King Y1 - 2002/10/01 UR - http://molpharm.aspetjournals.org/content/62/4/957.abstract N2 - The recombinant rat P2X5 (rP2X5) receptor, a poorly understood ATP-gated ion channel, was studied under voltage-clamp conditions and compared with the better understood homomeric rP2X1 receptor with which it may coexist in vivo. Expressed in defolliculated Xenopus laevis oocytes, rP2X5 responded to ATP with slowly desensitizing inward currents that, for successive responses, ran down in the presence of extracellular Ca2+ (1.8 mM). Replacement of Ca2+ with either Ba2+ or Mg2+prevented rundown, although agonist responses were very small, whereas reintroduction of Ca2+ for short periods of time (&lt;300 s) before and during agonist application yielded consistently larger responses. Using this Ca2+-pulse conditioning, rP2X5 responded to ATP and other nucleotides (ATP, 2-methylthio-ATP, adenosine-5′-O-(thiotriphosphate), 2′-&amp;-3′-O-(4-benzoylbenzoyl)-ATP, α,β-methylene-ATP, P1-P(4)-diadenosine-5′-phosphate, and more) with pEC50 values within 1 log unit of respective determinations for rP2X1. Only GTP was selective for rP2X5, although 60-fold less potent than ATP. At rP2X5, lowering extracellular pH reduced the potency and efficacy of ATP, whereas extracellular Zn2+ ions (0.1–1000 μM) potentiated then inhibited ATP responses in a concentration-dependent manner. However, these modulators affected rP2X1 receptors in subtly different ways–with increasing H+ and Zn2+ ion concentrations reducing agonist potency. For P2 receptor antagonists, the potency order at rP2X5 was pyridoxal-5-phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS) &gt; 2′,3′-O-(2,4,6-trinitrophenyl)ATP (TNP-ATP) &gt; suramin &gt; reactive blue 2 (RB-2) &gt; diinosine pentaphosphate (Ip5I). In contrast, the potency order at rP2X1was TNP-ATP = Ip5I &gt; PPADS &gt; suramin = RB-2. Thus, the Ca2+-sensitized homomeric rP2X5 receptor is similar in agonist profile to homomeric rP2X1—although it can be distinguished from the latter by GTP agonism, antagonist profile, and the modulatory effects of H+ and Zn2+ ions. ER -