Naturally-expressed nicotinic acetylcholine receptor subtypes

Abstract

Nicotinic acetylcholine receptors (nAChRs) warrant attention, as they play many critical roles in brain and body function and have been implicated in a number of neurological and psychiatric disorders, including nicotine dependence. nAChRs are composed as diverse subtypes containing specific combinations of genetically-distinct subunits and that have different functional properties, distributions, and pharmacological profiles. There had been confidence that the rules that define ranges of assembly partners for specific subunits were well-established, especially for the more prominent nAChR subtypes. However, we review here some newer findings indicating that nAChRs having largely the same, major subunits exist as isoforms with unexpectedly different properties. Moreover, we also summarize our own studies indicating that novel nAChR subtypes exist and/or have distributions not heretofore described. Importantly, the nAChRs that exist as new isoforms or subtypes or have interesting distributions require alteration in thinking about their roles in health and disease.

Fig. 1

Schematic illustrations are shown as viewed from synaptic space of selected nicotinic acetylcholine receptor (nAChR) subtypes, all of which are assembled as pentamers of subunits forming a rosette with a central pore, which is the ion channel. In the upper part of the figure are shown the presumed structures of: left - a homomeric α7-nAChR composed only of α7 subunits (blue) as found, for example, in the ventral tegmental area; right - a heteromeric α7β2-nAChR composed of α7 subunits (blue) and β2 subunits (gray) as found, for example, on basal forebrain cholinergic neurons except in mice lacking β2 subunits [91]. The heteromeric, presumably α7β2-nAChR subtype displays elevated sensitivity to functional blockade by β-amyloid or dihydro-β-erythrodine than seen for homomeric α7-nAChRs [91]. In the lower part of the figure are shown isoforms of α4β2-nAChRs having a 3:2 (left) or a 2:3 (right) ratio of α4:β2 subunits (α4 subunits, lavender). (α4)₃(β2)₂-nAChRs have comparatively low sensitivity to nicotinic agonists when compared to “high sensitivity,” (α4)₂(β2)₃-nAChRs [–12]. Studies based on heterozygotic mice with lower gene doses for nAChR α4 subunits indicate that proportions of functional expression of high sensitivity (α4)₂(β2)₃-nAChRs are decreased and that the opposite occurs in nAChR subunit β2+/− heterozygotic mice, suggesting that natural expression of these two isoforms occurs, could be regulated, and has physiological relevance [143].

Fig. 2

Diagram indicating some of the complexity in nicotinic acetylcholine receptor (nAChR) expression across cell types and at different locations relative to the synapse, using the ventral tegmental area (VTA) as an example. It has been known for some time that α7-nAChRs (turquoise) are present on glutamatergic nerve terminals (Glu, red) synapsing on dopaminergic (DA) cell bodies (and perhaps dendrites; DA, orange triangle) in the VTA [–5]. Moreover, different nAChRs, presumably responding to acetylcholine released from cholinergic nerve terminals (purple) have a variety of distributions on DA neurons in the VTA. In fact, it recently became clear that functional nAChR phenotypes allow “binning” of VTA DA type ID, type IID and type IIID neuronal subsets predominantly expressing, respectively, α4β2-nAChRs (lavender), α7-nAChRs (turquoise), or β4*-nAChRs (blue) on soma and/or dendrites [90]. This means that there isn’t just one kind of VTA DA neuron, at least with respect to nAChR expression profiles. Whether these VTA DA functional nAChR phenotypes change with nicotine exposure and/or are on VTA VDA neurons that also receive distinctive inputs or have different targets remains to be determined. Moreover, newly appreciated is the presence of α6*-nAChRs (green) not only on VTA DA nerve terminals ending in the NAc and perhaps on VTA soma (not shown in this illustration) [, –131], but also on GABAergic boutons (black) associated with VTA DA neuronal soma and/or proximal dendrites [122]. In addition, on GABAergic terminals, pre-terminals and/or soma, there are α4β2-nAChRs [144]. The balance between activation and desensitization or persistent inactivation of different nAChR subtypes on VTA nerve terminals ending on DA neurons and on those neurons and their own terminals likely dictates VTA DA neuronal activity relevant to nicotine dependence and perhaps to cholinergic control of dependence on other agents as well as more generally in mood and reward.