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The Journal of Neuroscience, October 29, 2008, 28(44):11131-11140; doi:10.1523/JNEUROSCI.2763-08.2008

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Cellular/Molecular
Opposite Effects of Zinc on Human and Rat P2X2 Receptors

Rachel K. Tittle and Richard I. Hume

Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109-1048

Correspondence should be addressed to Richard I. Hume, Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 830 North University Avenue, Ann Arbor, MI 48109-1048. Email: rhume{at}umich.edu

P2X2 receptors from rats show potentiation when a submaximal concentration of ATP is combined with zinc in the range of 10–100 µM. Alignment of the amino acid sequences of human P2X2 (hP2X2) and rat P2X2 (rP2X2) indicated that only one of two histidines essential for zinc potentiation in rP2X2 is present at the homologous position in hP2X2 (H132), with the position homologous to rat H213 instead having an arginine (R225). When expressed in Xenopus oocytes, mouse P2X2a and P2X2b receptors showed zinc potentiation indistinguishable from rat P2X2a, but hP2X2b receptors were inhibited by zinc. The extent of zinc inhibition of hP2X2b varied with the ATP concentration, with an IC50 of 8.4 µM zinc when ATP was applied at 10% of maximal and 87 µM zinc when ATP was applied at 99% of maximal. Site-directed mutagenesis showed that none of the nine histidines in the extracellular domain of hP2X2b were required for zinc inhibition, although inhibition was attenuated in the H204A and H209A mutations. Mutating R225 to a cysteine was sufficient to confer zinc potentiation onto hP2X2b, and zinc potentiation was absent in the hP2X2bH132A/R225C double mutant. This suggests that zinc potentiation in the mutant hP2X2b uses the same mechanism as zinc potentiation in wild-type rP2X2a. Because of the species-specific modulation by zinc, evidence for an in vivo role of P2X2 receptors based on studies conducted on genetically modified mice needs to be viewed with caution when extrapolations are made to the function of the human nervous system.

Key words: mice; ATP; purinergic receptor; zinc; receptor modulation; mouse P2X2

Received June 17, 2008; revised Aug. 17, 2008; accepted Sept. 16, 2008.

Correspondence should be addressed to Richard I. Hume, Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 830 North University Avenue, Ann Arbor, MI 48109-1048. Email: rhume{at}umich.edu






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