The α5 Nicotinic Acetylcholine Receptor Subunit Differentially Modulates α4β2* and α3β4* Receptors

Abstract

Nicotine, the principal reinforcing compound in tobacco, acts in the brain by activating neuronal nicotinic acetylcholine receptors (nAChRs). This review summarizes our current knowledge regarding how the α5 accessory nAChR subunit, encoded by the CHRNA5 gene, differentially modulates α4β2* and α3β4* receptors at the cellular level. Genome-wide association studies have linked a gene cluster in chromosomal region 15q25 to increased susceptibility to nicotine addiction, lung cancer, chronic obstructive pulmonary disease, and peripheral arterial disease. Interestingly, this gene cluster contains a non-synonymous single-nucleotide polymorphism (SNP) in the human CHRNA5 gene, causing an aspartic acid (D) to asparagine (N) substitution at amino acid position 398 in the α5 nAChR subunit. Although other SNPs have been associated with tobacco smoking behavior, efforts have focused predominantly on the D398 and N398 variants in the α5 subunit. In recent years, significant progress has been made toward understanding the role that the α5 nAChR subunit—and the role of the D398 and N398 variants—plays on nAChR function at the cellular level. These insights stem primarily from a wide range of experimental models, including receptors expressed heterologously in Xenopus oocytes, various cell lines, and neurons derived from human induced pluripotent stem cells (iPSCs), as well as endogenous receptors in genetically engineered mice and—more recently—rats. Despite providing a wealth of available data, however, these studies have yielded conflicting results, and our understanding of the modulatory role that the α5 subunit plays remains incomplete. Here, we review these reports and the various techniques used for expression and analysis in order to examine how the α5 subunit modulates key functions in α4β2* and α3β4* receptors, including receptor trafficking, sensitivity, efficacy, and desensitization. In addition, we highlight the strikingly different role that the α5 subunit plays in Ca2+ signaling between α4β2* and α3β4* receptors, and we discuss whether the N398 α5 subunit variant can partially replace the D398 variant.

α3β4∗ Nicotinic Acetylcholine Receptors Strongly Modulate the Excitability of VIP Neurons in the Mouse Inferior Colliculus

“…Application of the pharmacological approach used here to additional neuron types will help expand our understanding of the functional roles of α 3 β 4 * nAChRs in the IC. It is important to note that α 3 β 4 * nAChRs can have two stoichiometries, (α 3 β 4 ) 2 α 3 or (α 3 β 4 ) 2 β 4 , and can also combine with a different fifth subunit, (α 3 β 4 ) 2 X, where the fifth subunit can be α 2 , α 5 , α 6 , or β 3 (Scholze and Huck, 2020). Previous studies indicate that the exact subunit composition of an α 3 β 4 * nAChR has some effect on Ca 2+ permeability and desensitization rate, but generally little or no effect on the potency and efficacy of ACh (Wang et al, 1996;Gerzanich et al, 1998;Groot-Kormelink et al, 2001;Papke et al, 2010;Stokes and Papke, 2012).…”

CHRNA5links chandelier cells to severity of amyloid pathology in aging and Alzheimer’s Disease

“…Furthermore, as α4β2α5 nicotinic receptors support higher conductance of calcium ions into the cell (Scholze & Huck, 2020; Sciaccaluga et al, 2015), another putative neuroprotective mechanism of the α5 subunit may be through driving possible calcium-dependent pro-survival pathways in the neurons which express the α4β2α5 nicotinic receptors (Cingir Koker et al, 2018; Ueda et al, 2008).…”

α3β4* Nicotinic acetylcholine receptors strongly modulate the excitability of VIP neurons in the mouse inferior colliculus

“…It is important to note that α3β4* nAChRs can have two stoichiometries, (α3β4)2α3 or (α3β4)2β4, and can also combine with a different fifth subunit, (α3β4)2X, where the fifth subunit can be α2, α5, α6, or β3 (Scholze & Huck, 2020). Previous studies indicate that the exact subunit composition of an α3β4* nAChR has some effect on Ca 2+ permeability and desensitization rate, but generally little or no effect on the potency and efficacy of ACh (Wang et al, 1996;Gerzanich et al, 1998;Groot-Kormelink et al, 2001;Papke et al, 2010;Stokes & Papke, 2012).…”