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The Journal of Neuroscience, March 15, 2001, 21(6):1848-1856

Subunit-Dependent Modulation of Neuronal Nicotinic Receptors by Zinc

Bernard Hsiao, David Dweck, and Charles W. Luetje

Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, Florida 33101

We examined the effect of zinc on rat neuronal nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes as simple heteromers of 2, 3, or 4 and 2 or 4. Coapplication of zinc with low concentrations of acetylcholine (EC₁₀) resulted in differential effects depending on receptor subunit composition. The 22, 24, 34, 42, and 44 receptors exhibited biphasic modulation by zinc, with potentiation of the acetylcholine response occurring at 1-100 µM zinc and inhibition occurring at higher zinc concentrations. In contrast, 32 receptors were only inhibited by zinc (IC₅₀ = 97 ± 16 µM). The greatest potentiating effect of zinc was seen with 44 receptors that were potentiated to 560 ± 17% of the response to ACh alone, with an EC₅₀ of 22 ± 4 µM zinc. Cadmium, but not nickel, was also able to potentiate 44 receptors. Both zinc potentiation of 44 receptors and zinc inhibition of 32 receptors were voltage independent. The sensitivity of zinc potentiation of 44 to diethylpyrocarbonate treatment and alterations in pH suggested the involvement of histidine residues. Zinc continued to inhibit 44 and 32 after diethylpyrocarbonate treatment. Application of a potentiating zinc concentration increased the response of 42 and 44 receptors to saturating ACh concentrations. The rate of Ach-induced desensitization of these receptors was unaffected by zinc. Our results reveal zinc potentiation as a new mode of neuronal nAChR modulation.

Key words: neuronal nicotinic receptors; zinc; potentiation; inhibition; modulation; acetylcholine

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2161848-09$05.00/0

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