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Papers In Press, published online ahead of print June 20, 2003
Department of Physiology, University of Chile, Santiago 6513492
Corresponding Author: jphuid{at}genes.bio.puc.cl
To elucidate the role of extracellular histidines in the modulation of the rat P2X44 receptor by trace metals, we generated single, double, and triple histidine mutants for residues 140, 241, and 286, replacing them with alanines. cDNAs for the wild-type and receptor mutants were expressed in Xenopus laevis oocytes and in HEK 293 cells and examined by the two electrode and patch clamp techniques, respectively. While copper inhibited concentration-dependently the ATP-gated currents in the wild-type and in the single or double H241A and H286A receptor mutants, all receptors containing H140A were insensitive to copper in both cell systems. The characteristic bell-shaped concentration-response curve of zinc observed in the wild-type receptor became sigmoid in both oocytes and HEK cells expressing the H140A mutant; in these mutants, the zinc potentiation was 2.5-4 fold larger than in the wild-type. Results with the H140T and H140R mutants further support the importance of a histidine residue at this position. We conclude that His-140 is critical for the action of copper, indicating that this histidine residue, but not His-241 nor His-286, forms part of the inhibitory allosteric metal binding site of the P2X44 receptor, which is distinct from the putative zinc facilitator binding site.
J. Biol. Chem, 10.1074/jbc.M305177200
Submitted on May 16, 2003
Revised on June 20, 2003
Accepted on June 20, 2003
Histidine 140 plays a key role in the inhibitory modulation of the P2X44 nucleotide receptor by copper but not zinc
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