Determinants of zinc potentiation on the α4 subunit of neuronal nicotinic receptors

Bernard Hsiao, Karla B. Mihalak, Sarah E. Repicky, Drew Everhart, Ana H. Mederos, Arun Malhotra, Charles W. Luetje

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


We have shown previously that the function of neuronal nicotinic acetylcholine receptors can be modulated by zinc. This modulation varies from potentiation to inhibition, depending on receptor subunit composition and zinc concentration, with the α4β2 and α4β4 receptors displaying the most dramatic potentiation. In this study, we used site-directed mutagenesis to identify glutamate 59 and histidine 162 on the rat α4 subunit as potential mediators of zinc potentiation. By modeling the extracellular domain of the receptor pentamer, we locate these residues to two subunit-subunit interfaces that alternate with the two acetylcholine-binding interfaces. Substitution of a cysteine at either position allows additional reduction of zinc potentiation upon treatment with the methanethiosulfonate reagents N-biotinoylaminoethyl methanethiosulfonate (MTSEA-biotin) and [2-(trimethylammonium)ethyl] methanethiosulfonate. Mutagenesis and methanethiosulfonate treatment are most effective at position 162, and the presence of zinc hinders the reaction of MTSEA-biotin with the substituted cysteine at this position, suggesting that α4His162 participates in forming a coordination site for zinc. Mutagenesis and methanethiosulfonate treatment are less effective at position 59, suggesting that whereas α4Glu59 may be near the zinc coordination site, it may not be participating in coordination of the zinc ion. It is noteworthy that the position of α4Glu59 within the neuronal nAChR is identical to that of a residue that lines the benzodiazepine-binding site on GABAA receptors. We suggest that the zinc potentiation sites on neuronal nAChRs are structurally and functionally similar to the benzodiazepine-binding sites on GABAA receptors.

Original languageEnglish (US)
Pages (from-to)27-36
Number of pages10
JournalMolecular Pharmacology
Issue number1
StatePublished - Jan 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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