Abstract
We examined the effect of zinc on rat neuronal nicotinic acetylcholine receptors (nAChRs) expressed in
Xenopus
oocytes as simple heteromers of α2, α3, or α4 and β2 or β4. Coapplication of zinc with low concentrations of acetylcholine (≤EC
10
) resulted in differential effects depending on receptor subunit composition. The α2β2, α2β4, α3β4, α4β2, and α4β4 receptors exhibited biphasic modulation by zinc, with potentiation of the acetylcholine response occurring at 1–100 μ
m
zinc and inhibition occurring at higher zinc concentrations. In contrast, α3β2 receptors were only inhibited by zinc (IC
50
= 97 ± 16 μ
m
). The greatest potentiating effect of zinc was seen with α4β4 receptors that were potentiated to 560 ± 17% of the response to ACh alone, with an EC
50
of 22 ± 4 μ
m
zinc. Cadmium, but not nickel, was also able to potentiate α4β4 receptors. Both zinc potentiation of α4β4 receptors and zinc inhibition of α3β2 receptors were voltage independent. The sensitivity of zinc potentiation of α4β4 to diethylpyrocarbonate treatment and alterations in pH suggested the involvement of histidine residues. Zinc continued to inhibit α4β4 and α3β2 after diethylpyrocarbonate treatment. Application of a potentiating zinc concentration increased the response of α4β2 and α4β4 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.
