Extracellular histidine residues identify common structural determinants in the copper/zinc P2X<sub>2</sub> receptor modulation

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dc.contributor.authorLorca, RA
dc.contributor.authorCoddou, C
dc.contributor.authorGazitúa, MC
dc.contributor.authorBull, P
dc.contributor.authorArredondo, C
dc.contributor.authorHuidobro-Toro, JP
dc.date.accessioned2025-01-21T01:06:42Z
dc.date.available2025-01-21T01:06:42Z
dc.date.issued2005
dc.description.abstractTo assess the mechanism of P2X(2) receptor modulation by transition metals, the cDNA for the wild-type receptor was injected to Xenopus laevis oocytes and examined 48-72 h later by the two-electrode voltage-clamp technique. Copper was the most potent of the trace metals examined; at 10 mu M it evoked a 25-fold potentiation of the 10 mu M ATP-gated currents. Zinc, nickel or mercury required 10-fold larger concentrations to cause comparable potentiations, while palladium, cobalt or cadmium averaged only 12- and 3-fold potentiations, respectively. Platinum was inactive. The non-additive effect of copper and zinc at 10-100 mu M suggests a common site of action; these metals also shifted to the left the ATP concentration-response curves. To define residues necessary for trace metal modulation, alanines were singly substituted for each of the nine histidines in the extracellular domain of the rat P2X(2) receptor. The H120A and H213A mutants were resistant to the modulator action of copper, zinc and other metals with the exception of mercury. Mutant H192A showed a reduction but not an abrogation of the copper or zinc potentiation. H245A showed less affinity for copper while this mutant flattened the zinc-induced potentiation. Mutant H319A reduced the copper but not the zinc-induced potentiation. In contrast, mutants H125A, H146A, H152A and H174A conserved the wild-type receptor sensitivity to trace metal modulation. We propose that His120, His192, His213 and His245 form part of a common allosteric metal-binding site of the P2X(2) receptor, which for the specific coordination of copper, but not zinc, additionally involves His319.
dc.fuente.origenWOS
dc.identifier.doi10.1111/j.1471-4159.2005.03387.x
dc.identifier.eissn1471-4159
dc.identifier.issn0022-3042
dc.identifier.urihttps://doi.org/10.1111/j.1471-4159.2005.03387.x
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/96206
dc.identifier.wosidWOS:000232142900020
dc.issue.numero2
dc.language.isoen
dc.pagina.final512
dc.pagina.inicio499
dc.revistaJournal of neurochemistry
dc.rightsacceso restringido
dc.subjectallosteric metal modulation
dc.subjectextracellular histidines
dc.subjectP2X(2) metal coordination complexes
dc.subjectP2X(2) receptor
dc.subjectsite-directed mutagenesis
dc.subjecttrace metal modulation
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleExtracellular histidine residues identify common structural determinants in the copper/zinc P2X<sub>2</sub> receptor modulation
dc.typeartículo
dc.volumen95
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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