期刊
NEUROPHARMACOLOGY
卷 54, 期 8, 页码 1189-1200出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2008.03.010
关键词
voltage clamp; Xenopus oocytes; nicotine dependence
资金
- NIDA NIH HHS [U19 DA017548-05, DA017548, U19 DA017548] Funding Source: Medline
- NIGMS NIH HHS [GM57481, GM48677, P01 GM048677-160012, P01 GM048677, R01 GM057481-07, R01 GM057481] Funding Source: Medline
- NIMH NIH HHS [MH53631, R01 MH053631, R29 MH053631, R01 MH053631-13, R01 MH053631-11S1] Funding Source: Medline
Heterologous expression systems have increased the feasibility of developing selective ligands to target nicotinic acetylcholine receptor (nAChR) subtypes. However, the alpha 6 subunit, a component in nAChRs that mediates some of the reinforcing effects of nicotine, is not easily expressed in systems such as the Xenopus oocyte. Certain aspects of alpha 6-containing receptor pharmacology have been studied by using chimeric subunits containing the alpha 6 ligand-binding domain. However, these chimeras would not be sensitive to an alpha 6-selective channel blocker; therefore we developed an alpha 6 chimera (alpha 4/6) that has the transmembrane and intracellular domains of alpha 3 and the extracellular domain of alpha 4. We examined the pharmacological properties of alpha 4/6-containing receptors and other important nAChR subtypes, including alpha 7, alpha 4 beta 2, alpha 4 beta 4, alpha 3 beta 4, alpha 3 beta 2, and alpha 3 beta 2 beta 3, as well as receptors containing alpha 6/3 and alpha 6/4 chimeras. Our data show that the absence or presence of the beta 4 subunit is an important factor for sensitivity to the ganglionic blocker mecamylamine, and that dihydro-beta-erythroidine is most effective on subtypes containing the alpha 4 subunit extracellular domain. Receptors containing the alpha 6/4 subunit are sensitive to alpha-conotoxin PIA, while receptors containing the reciprocal alpha 4/6 chimera are insensitive. In experiments with novel antagonists of nicotine-evoked dopamine release, the alpha 4/6 chimera indicated that structural rigidity was a key element of compounds that could result in selectivity for noncompetitive inhibition of alpha 6 containing receptors. Our data extend the information available on prototypical nAChR antagonists, and establish the alpha 4/6 chimera as a useful new tool for screening drugs as selective nAChR antagonists. (c) 2008 Elsevier Ltd. All rights reserved.
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