| Determinants of zinc potentiation on the alpha4 subunit of neuronal nicotinic receptors. | |
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MedLine Citation:
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PMID: 16189299 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 alpha4beta2 and alpha4beta4 receptors displaying the most dramatic potentiation. In this study, we used site-directed mutagenesis to identify glutamate 59 and histidine 162 on the rat alpha4 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 alpha4His162 participates in forming a coordination site for zinc. Mutagenesis and methanethiosulfonate treatment are less effective at position 59, suggesting that whereas alpha4Glu59 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 alpha4Glu59 within the neuronal nAChR is identical to that of a residue that lines the benzodiazepine-binding site on GABA(A) receptors. We suggest that the zinc potentiation sites on neuronal nAChRs are structurally and functionally similar to the benzodiazepine-binding sites on GABA(A) receptors. |
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Authors:
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Bernard Hsiao; Karla B Mihalak; Sarah E Repicky; Drew Everhart; Ana H Mederos; Arun Malhotra; Charles W Luetje |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2005-09-27 |
Journal Detail:
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Title: Molecular pharmacology Volume: 69 ISSN: 0026-895X ISO Abbreviation: Mol. Pharmacol. Publication Date: 2006 Jan |
Date Detail:
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Created Date: 2005-12-29 Completed Date: 2006-02-07 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0035623 Medline TA: Mol Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 27-36 Citation Subset: IM |
Affiliation:
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Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL 33101, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Animals Binding Sites Calcium / metabolism Ion Channel Gating Molecular Sequence Data Neurons / drug effects*, metabolism Receptors, Nicotinic / drug effects*, metabolism, physiology Sequence Homology, Amino Acid Xenopus laevis Zinc / pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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DA08102/DA/NIDA NIH HHS; GM069972/GM/NIGMS NIH HHS; MH66038/MH/NIMH NIH HHS; T32 HL07188/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Receptors, Nicotinic; 7440-66-6/Zinc; 7440-70-2/Calcium |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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