Browsing by Author "Chacón, M"

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    The human prion octarepeat fragment prevents and reverses the inhibitory action of copper in the P2X4 receptor without modifying the zinc action
    (2003) Lorca, RA; Chacón, M; Barría, MI; Inestrosa, NC; Huidobro-Toro, JP
    Human prion protein fragments (PrP60-67 or PrP59-91) prevented and reversed the inhibition elicited by 5 mum copper on the P2X(4) receptor expressed in Xenopus laevis oocytes. A 60-s pre-application of 5 muM copper caused a 69.2 +/- 2.6% inhibition of the 10 muM adenosine triphosphate (ATP)-evoked currents, an effect that was prevented by mixing 5 muM copper with 0.01-10 muM of the PrP fragments 1-min prior to application. This interaction was selective, as PrP59-91 did not alter the facilitatory action of zinc. The EC50 of PrP60-67 and PrP59-91 for the reduction of the copper inhibition were 4.6 +/- 1 and 1.3 +/- 0.4 muM, respectively. A synthetic PrP59-91 variant in which all four His were replaced by Ala was inactive. However, the replacement of Trp in each of the four putative copper-binding domains by Ala slightly decreased its potency. Furthermore, the application of 10 muM PrP59-91 reversed the copper-evoked inhibition, restoring the ATP concentration curve to the same level as the non-inhibited state. Fragment 139-157 of betaA4 amyloid precursor protein also prevented the action of copper; its EC50 was 1.6 +/- 0.1 muM; the metal chelator penicillamine was equipotent with PrP60-67, but carnosine was significantly less potent. Our findings highlight the role of PrP in copper homeostasis and hint at its possible role as a modulator of synapses regulated by this trace metal.