Effects of Zn2+ on wild and mutant neuronal α7 nicotinic receptors

E. Palma, L. Maggi, R. Miledi, F. Eusebi

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Zn2+ is a key structural/functional component of many proteins and is present at high concentrations in the brain and retina, where it modulates ligand-gated receptors. Therefore, a study was made of the effects of zinc on homomeric neuronal nicotinic receptors expressed in Xenopus oocytes after injection of cDNAs encoding the chicken wild or mutant α7 subunits. In oocytes expressing wild-type receptors, Zn2+ alone did not elicit appreciable membrane currents. Acetylcholine (AcCho) elicited large currents (I(AcCho)) that were reduced by Zn2+ in a reversible and dose-dependent manner, with an IC50 of 27 μM and a Hill coefficient of 0.4. The inhibition of I(AcCho) by Zn2+ was competitive and voltage-independent, a behavior incompatible with a channel blockade mechanism. In sharp contrast, in oocytes expressing a receptor mutant, with a threonine-for-leucine 247 substitution (L247Tα7), subnanomolar concentrations of Zn2+ elicited membrane currents (I(Zn)) that were reversibly inhibited by the nicotinic receptor blockers methyllycaconitine and α-bungarotoxin. Cell-attached single-channel recordings showed that Zn2+ opened channels that had a mean open time of 5 ms and a conductance of 48 pS. At millimolar concentrations Zn2+ reduced I(AcCho) and the block became stronger with cell hyperpolarization. Thus, Zn2+ is a reversible blocker of wild-type α7 receptors, but becomes an agonist, as well as an antagonist, following mutation of the highly conserved leucine residue 247 located in the M2 channel domain. We conclude that Zn2+ is a modulator as well as an activator of homomeric nicotinic α7 receptors.

Original languageEnglish
Pages (from-to)10246-10250
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number17
Publication statusPublished - Aug 18 1998

ASJC Scopus subject areas

  • General
  • Genetics


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