Functional characterization of the α5(Asn398) variant associated with risk for nicotine dependence in the α3β4α5 nicotinic receptor

Ping Li, Megan McCollum, John Bracamontes, Joe Henry Steinbach, Gustav Akk

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Smoking is a major cause for premature death. Work aimed at identifying genetic factors that contribute to nicotine addiction has revealed several single nucleotide polymorphisms (SNPs) that are linked to smoking-related behaviors such as nicotine dependence and level of smoking. One of these SNPs leads to an aspartic acid-to-asparagine substitution in the nicotinic receptor α5 subunit at amino acid position 398 [rs16969968; α5(Asn398)]. The α5 subunit is expressed both in the brain and in the periphery. In the brain, it associates with the α4 and β2 subunits to form α4β2α5 receptors. In the periphery, the α5 subunit combines with the α3 and β4 subunits to form the major ganglionic postsynaptic nicotinic receptor subtype. The α3β4α5 receptor regulates a variety of autonomic responses such as control of cardiac rate, blood pressure, and perfusion. In this paradigm, the α5(Asn398) variant may act by regulating autonomic responses that may affect nicotine intake by humans. Here, we have investigated the effect of the α5(Asn398) variant on the function of the α3β4α5 receptor. The wild-type or variant α5 subunits were coexpressed with the α3 and β4 subunits in human embryonic kidney 293 cells. The properties of the receptors were studied using whole-cell and single-channel electrophysiology. The data indicate that the introduction of the α5(Asn398) mutation has little effect on the pharmacology of receptor activation, receptor desensitization, or single-channel properties. We propose that the effect of the α5(Asn398) variant on nicotine use is not mediated by an action on the physiological or pharmacological properties of the α3β4α5 subtype.

Original languageEnglish
Pages (from-to)818-827
Number of pages10
JournalMolecular pharmacology
Volume80
Issue number5
DOIs
StatePublished - Nov 1 2011

Fingerprint Dive into the research topics of 'Functional characterization of the α5(Asn398) variant associated with risk for nicotine dependence in the α3β4α5 nicotinic receptor'. Together they form a unique fingerprint.

  • Cite this