Unliganded human mutant alpha 7 nicotinic receptors are modulated by Ca2+ and trace levels of Zn2+.
A large body of evidence indicates that ligand-gated channels may open spontaneously, exhibiting a basal activity in the absence of the neurotransmitter. In the present work, we were interested in studying the Ca(2+)-induced modulation of the basal channel activity of unliganded human L248Talpha7 receptors expressed in Xenopus oocytes. While the basal channel activity was blocked by either the nicotinic antagonist methyllycaconitine or the superfusion with a Ca(2+)-free medium, it was enhanced by increasing external Ca2+ concentrations. External Ca2+ significantly influenced the channel properties lengthening the channel duration and reducing the channel conductance, in a dose dependent manner. Furthermore, the basal channel activity in standard medium was blocked by N,N,N',N'-tetrakis-2-pyridylmethyl-ethylenediamine, the chelator of divalent cations with very high affinity for Zn2+, and was induced by Zn2+ when Ca2+ was present in the external medium. We conclude that basal activity of alpha7 mutant receptor-channels is caused by divalent cation contaminants present in the external medium, namely Zn2+; is positively modulated by the external Ca2+; and is inhibited when Ca2+ is absent from the medium. The patho-physiological consequences of these findings are discussed.
Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Fisiologia Umana e Farmacologia, Centro di Eccellenza BEMM, Università di Roma La Sapienza, P.le A. Moro 5, I-00185 Rome, Italy.
Raffaella
R
Tonini
Massimiliano
M
Renzi
Fabrizio
F
Eusebi
D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D009154:Mutation / Q000235:genetics / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000235:genetics / Q000502:physiology*; D014981:Xenopus; D015032:Zinc / Q000494:pharmacology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579167:Chrna7 protein, human; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D015032:Zinc; D002118:Calcium