title: Functional characterization of the α5(Asn398) variant associated with risk for nicotine dependence in the α3β4α5 nicotinic receptor.
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.
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Megan
authors.initials: M
authors.lastname: McCollum
authors.forename: John
authors.initials: J
authors.lastname: Bracamontes
authors.forename: Joe Henry
authors.initials: JH
authors.lastname: Steinbach
authors.forename: Gustav
authors.initials: G
authors.lastname: Akk
mesh_terms: D002460:Cell Line; D006801:Humans; D018408:Patch-Clamp Techniques; D020641:Polymorphism, Single Nucleotide; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4