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The role of histidine residues in modulation of the rat P2X(2) purinoceptor by zinc and pH.
Clyne JD
,
LaPointe LD
,
Hume RI
.
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P2X(2) receptor currents are potentiated by acidic pH and zinc. To identify residues necessary for proton and zinc modulation, alanines were singly substituted for each of the nine histidines in the extracellular domain of the rat P2X(2) receptor. Wild-type and mutant receptors were expressed in Xenopus oocytes and analysed with two-electrode voltage clamp. All mutations caused less than a 2-fold change in the EC(50) of the ATP concentration-response relation. Decreasing the extracellular pH from 7.5 to 6.5 potentiated the responses to 10 microM ATP of wild-type P2X(2) and eight mutant receptors more than 4-fold, but the response of the mutant receptor H319A was potentiated only 1.4-fold. The H319A mutation greatly attenuated the maximal potentiation that could be produced by a drop in pH, shifted the pK(a) (-log of dissociation constant) of the potentiation to a more basic pH as compared with P2X(2) and revealed a substantial pH-dependent decrease in the maximum response with a pK(a) near 6.0. Substituting a lysine for H319 reduced the EC(50) for ATP 40-fold. Zinc (20 microM) potentiated the responses to 10 microM ATP of wild-type P2X(2) and seven histidine mutants by approximately 8-fold but had virtually no effect on the responses of two mutants, H120A and H213A. Neither H120A nor H213A removed the voltage-independent inhibition caused by high concentrations of zinc. The observation that different mutations selectively eliminated pH or zinc potentiation implies that there are two independent sites of action, even though the mechanisms of pH and zinc potentiation appear similar.
Acuña-Castillo,
Zinc and copper modulate differentially the P2X4 receptor.
2000, Pubmed,
Xenbase
Acuña-Castillo,
Zinc and copper modulate differentially the P2X4 receptor.
2000,
Pubmed
,
Xenbase
Alberty,
Effect of pH and metal ion concentration on the equilibrium hydrolysis of adenosine triphosphate to adenosine diphosphate.
1968,
Pubmed
Brake,
New structural motif for ligand-gated ion channels defined by an ionotropic ATP receptor.
1994,
Pubmed
,
Xenbase
Brake,
Signaling by extracellular nucleotides.
1996,
Pubmed
Brooks,
Bound and determined: a computer program for making buffers of defined ion concentrations.
1992,
Pubmed
Burnstock,
Purine-mediated signalling in pain and visceral perception.
2001,
Pubmed
Chesler,
The regulation and modulation of pH in the nervous system.
1990,
Pubmed
Choi,
Identification and mechanism of action of two histidine residues underlying high-affinity Zn2+ inhibition of the NMDA receptor.
1999,
Pubmed
,
Xenbase
Christianson,
Structural biology of zinc.
1991,
Pubmed
Clarke,
Mutation of histidine 286 of the human P2X4 purinoceptor removes extracellular pH sensitivity.
2000,
Pubmed
,
Xenbase
Colquhoun,
Binding, gating, affinity and efficacy: the interpretation of structure-activity relationships for agonists and of the effects of mutating receptors.
1998,
Pubmed
Ding,
Single channel properties of P2X2 purinoceptors.
1999,
Pubmed
,
Xenbase
Harvey,
Identification of an inhibitory Zn2+ binding site on the human glycine receptor alpha1 subunit.
1999,
Pubmed
Ho,
Site-directed mutagenesis by overlap extension using the polymerase chain reaction.
1989,
Pubmed
Housley,
Physiological effects of extracellular nucleotides in the inner ear.
2000,
Pubmed
Kanjhan,
Distribution of the P2X2 receptor subunit of the ATP-gated ion channels in the rat central nervous system.
1999,
Pubmed
Kao,
Salt effects on ionization equilibria of histidines in myoglobin.
2000,
Pubmed
Khakh,
Molecular physiology of P2X receptors and ATP signalling at synapses.
2001,
Pubmed
King,
Full sensitivity of P2X2 purinoceptor to ATP revealed by changing extracellular pH.
1996,
Pubmed
,
Xenbase
King,
Coexpression of rat P2X2 and P2X6 subunits in Xenopus oocytes.
2000,
Pubmed
,
Xenbase
King,
Effects of extracellular pH on agonism and antagonism at a recombinant P2X2 receptor.
1997,
Pubmed
,
Xenbase
Lê,
Central P2X4 and P2X6 channel subunits coassemble into a novel heteromeric ATP receptor.
1998,
Pubmed
,
Xenbase
Li,
Proton potentiation of ATP-gated ion channel responses to ATP and Zn2+ in rat nodose ganglion neurons.
1996,
Pubmed
Lynch,
Molecular and functional characterization of human P2X(2) receptors.
1999,
Pubmed
,
Xenbase
Nakazawa,
Effects of neuroamines and divalent cations on cloned and mutated ATP-gated channels.
1997,
Pubmed
,
Xenbase
Nakazawa,
pH dependence of facilitation by neurotransmitters and divalent cations of P2X2 purinoceptor/channels.
1997,
Pubmed
,
Xenbase
Orioli,
X-ray structure of the ternary complex Zn(II)-ATP-2,2'-bipyridyl and possible model for ATP transport.
1980,
Pubmed
Paoletti,
Molecular organization of a zinc binding n-terminal modulatory domain in a NMDA receptor subunit.
2000,
Pubmed
,
Xenbase
Ralevic,
Receptors for purines and pyrimidines.
1998,
Pubmed
Reeh,
Tissue acidosis in nociception and pain.
1996,
Pubmed
Smart,
Modulation of inhibitory and excitatory amino acid receptor ion channels by zinc.
1994,
Pubmed
Stoop,
Different sensitivities to pH of ATP-induced currents at four cloned P2X receptors.
1997,
Pubmed
Tanokura,
1H-NMR study on the tautomerism of the imidazole ring of histidine residues. I. Microscopic pK values and molar ratios of tautomers in histidine-containing peptides.
1983,
Pubmed
Thomas,
ATP as a mediator of mammalian central CO2 chemoreception.
2000,
Pubmed
Wang,
A single histidine residue is essential for zinc inhibition of GABA rho 1 receptors.
1995,
Pubmed
,
Xenbase
Wildman,
Zn2+ modulation of ATP-responses at recombinant P2X2 receptors and its dependence on extracellular pH.
1998,
Pubmed
,
Xenbase
Wildman,
Modulation of ATP-responses at recombinant rP2X4 receptors by extracellular pH and zinc.
1999,
Pubmed
,
Xenbase
Wildman,
Potentiation of ATP-responses at a recombinant P2x2 receptor by neurotransmitters and related substances.
1997,
Pubmed
,
Xenbase
Wildman,
Modulatory activity of extracellular H+ and Zn2+ on ATP-responses at rP2X1 and rP2X3 receptors.
1999,
Pubmed
,
Xenbase
Wooltorton,
Identification of a Zn2+ binding site on the murine GABAA receptor complex: dependence on the second transmembrane domain of beta subunits.
1997,
Pubmed
,
Xenbase
Xiong,
Differential modulation by copper and zinc of P2X2 and P2X4 receptor function.
1999,
Pubmed
,
Xenbase
Zhou,
Two mechanisms for inward rectification of current flow through the purinoceptor P2X2 class of ATP-gated channels.
1998,
Pubmed
,
Xenbase
Zhou,
Identification of a site that modifies desensitization of P2X2 receptors.
1998,
Pubmed
,
Xenbase
