Identification of a novel complement-dependent serum-elicited inward current in the Xenopus oocyte provoking Ca2+ influx and subsequent activation of Cl- channels

Philip Newsholme, Michael L. J. Ashford, C. Nicholas Hales

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    The membrane spanning complement channel is assumed to be a nonselective ion 'pore', although little evidence is available to support this hypothesis. In this paper we provide evidence that Ca2+ entry and Cl- exit occur rapidly after complement activation and precede the development of a long-lasting complement-dependent inward current. Addition of rabbit serum (a source of heterologous complement) and mouse anti-human insulin receptor antibody to a single Xenopus oocyte expressing human insulin receptor was shown to stimulate an initial hyperpolarising current followed by a sustained depolarising current. On voltage clamping the oocyte, a novel long-lasting inward current generated by serum addition was detected. Complement classical pathway-stimulated calcium influx into the oocyte was directly demonstrated using 45Ca influx measurements. In addition, we found that Ca2+ influx was required for the stimulation of the complement alternative pathway-dependent inward current. The novel conductance elicited by the classical pathway was outwardly rectifying, had a reversal potential of -35 ± 8 mV (or -52 ± 7 mV in the presence of chloride channel inhibitors), was inhibited by nifedipine, and was observed in the presence but not in the absence of the pore-forming complement component C9. As overactivation of complement does play a role in many inflammatory or autoimmune diseases, inhibition of early complement-mediated ion flux might restrict tissue damage and aid recovery from such diseases.

    Original languageEnglish
    Pages (from-to)491-501
    Number of pages11
    JournalBiochemical Pharmacology
    Issue number5
    Publication statusPublished - 1 Mar 1999

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