The Road to Discovery of Neuronal Nicotinic Cholinergic Receptor Subtypes

Abstract

The discovery that mammalian brain expresses the mRNAs for nine different nicotinic cholinergic receptor subunits (alpha2-alpha7, beta2-beta4) that form functional receptors when expressed in Xenopus laevis oocytes suggests that many different types of nicotinic cholinergic receptors (nAChRs) might be expressed in the mammalian brain., Using an historical approach, this chapter reviews some of the progress made in identifying the nAChR subtypes that seem to play a vital role in modulating dopaminergic function. nAChR subtypes that are expressed in dopamine neurons, as well as neurons that interact with dopamine neurons (glutamatergic, GABAergic), serve as the focus of this review. Subjects that are highlighted include the discovery of a low affinity alpha4beta2* nAChR, the identity of recently characterized alpha6* nAChRs, and the finding that these alpha6* receptors have the highest affinity for receptor activation of any of the native receptors that have been characterized to date. Topics that have been ignored in other recent reviews of this area, such as the discovery and potential importance of alternative transcripts, are presented along with a discussion of their potential importance.

Protein kinase C epsilon modulates nicotine consumption and dopamine reward signals in the nucleus accumbens

“…Nine different nAChR subunits are found in the mammalian brain (α 2-7 and β 2-4 ), and nAChRs can be either heteromeric, containing α-and β-subunits, or homomeric, comprising α 7 -subunits only (26). Heteromeric nAChRs, but not homomeric α 7 nAChRs, are critical for nicotine consumption (27) and reward (28) in mice.…”

In vitro exposure to nicotine induces endocytosis of presynaptic AMPA receptors modulating dopamine release in rat nucleus accumbens nerve terminals

“…However, the possibility that the desensitization of nAChRs may play a role in the decrease of AMPA responses cannot be excluded (Lin et al, 2010). Due to the very heterogeneous presence of nAChRs on these nerve endings (Wilkie et al, 1996;Sershen et al, 1997;Wonnacott, 1997;Kulak et al, 2001;Zoli et al, 2002;Collins et al, 2009;McClure-Begley et al, 2009;Grady et al, 2010;Wu and Lukas, 2011;Quik et al, 2011), it is very difficult to correlate specific nAChR subtypes with the internalization of AMPA receptors. Of course, the possibility that nAChR and AMPA receptors might not coexist on GABAergic and cholinergic nerve endings has to be also considered.…”

Merging old and new perspectives on nicotinic acetylcholine receptors

“…Additionally, nicotine will affect all of the many different nAChR subtypes in brain to varying degrees. Such varying effects of nicotine have been characterized using both ex vivo preparations of native rodent receptors [44] and pure populations of heterologously expressed human nAChRs [45] in vitro. However, the conclusions derived from the majority of these preclinical studies are compromised because of a mismatch between how nicotine reaches the receptors in a typical experimental protocol and how much more slowly it reaches receptors in the brain [41].…”