Reduced α4 subunit expression in α4+- and α4+- /ß2+- nicotinic acetylcholine receptors alters α4ß2 subtype up-regulation following chronic nicotine treatment.
Br J Pharmacol
; 175(11): 1944-1956, 2018 06.
Article
em En
| MEDLINE
| ID: mdl-28585241
ABSTRACT
BACKGROUND AND PURPOSE:
Genomic analysis has shown many variants in both CHRNA4 and CHRNB2, genes which encode the α4 and ß2 subunits of nicotinic ACh receptors (nAChR) respectively. Some variants influence receptor expression, raising the possibility that CHRNA4 variants may affect response to tobacco use in humans. Chronic exposure to nicotine increases expression of nAChRs, particularly α4ß2-nAChRs, in humans and laboratory animals. Here, we have evaluated whether the initial level of receptor expression affects the increase in expression. EXPERIMENTALAPPROACH:
Mice differing in expression of α4 and/or ß2 nAChR subunits were chronically treated with saline, 0.25, 1.0 or 4.0 mg·kg-1 ·h-1 nicotine. Brain preparations were analysed autoradiographically by [125 I]-epibatidine binding, immunoprecipitation and Western blotting. KEYRESULTS:
Immunochemical studies confirmed that most of the [3 H]-epibatidine binding corresponds to α4ß2*-nAChR and that increases in binding correspond to increases in α4 and ß2 proteins. Consistent with previous reports, the dose-dependent increase in nAChR in wild-type mice following chronic nicotine treatment, measured with any of the methods, reached a maximum. Although receptor expression was reduced by approximately 50% in ß2+- mice, the pattern of response to chronic treatment resembled that of wild-type mice. In contrast, both α4+- and α4+- /ß2+- exhibited relatively greater up-regulation. Consistent with previous reports, α4ß2α5-nAChR did not increase in response to nicotine. CONCLUSIONS AND IMPLICATIONS These results indicate that mice with reduced expression of the α4 nAChR subunit have a more robust response to chronic nicotine than mice with normal expression of this subunit. LINKED ARTICLES This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http//onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Regulação para Cima
/
Receptores Nicotínicos
/
Nicotina
Limite:
Animals
Idioma:
En
Revista:
Br J Pharmacol
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Itália