The road to discovery of neuronal nicotinic cholinergic receptor subtypes - PubMed (original) (raw)

Review

The road to discovery of neuronal nicotinic cholinergic receptor subtypes

Allan C Collins et al. Handb Exp Pharmacol. 2009.

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.

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Figures

Fig. 1

Binding of [3H]-epibatidine to membranes prepared from mouse brain. a depicts results of an experiment where varying concentrations of [3H]-epibatidine were incubated with membranes prepared from whole mouse brain under equilibrium binding conditions (see Marks et al. 2006, for specifics of the assay). As concentration increased, saturation was achieved, but as is most readily seen by Scatchard analysis (inset); the data were best fit by a two-site model. b (higher affinity) and c (lower affinity) provide the results of competition binding experiments. The data presented in b show that the addition of varying concentrations of unlabeled cytisine to incubations that contained either 0.3 nM [3H]-epibatidine (a concentration that fully saturates the high affinity epibatidine binding site) or 10nM [3H]-epibatidine (saturates the low affinity site) results in total inhibition of binding. However, more than 4 log units of cytisine were required to completely inhibit binding, leading to the conclusion that [3H]-epibatidine binds to at least two nAChR subtypes that differ in affinity for cytisine (i.e., cytisine-sensitive and cytisine-resistant). c depicts the results of similar experiments that used d-tubocurarine to inhibit [3H]-epibatidine binding

Fig. 2

Agonist-stimulated 86Rb+ from mouse brain synaptosomes. Acetylcholine (ACh)-stimulated ion (86Rb+) efflux from synaptosomes prepared from mouse brain was done as described in Marks et al. (2007). The left panel of this figure demonstrates that 4 log units of agonist (ACh) were required to elicit maximal ion flux. These data are fit best by a two-site model indicating that higher and lower sensitivity components of the ion flux response exist. The right hand panels of the figure illustrate the effects of α4 and β gene deletion on the ion flux responses. Both α4 and β2 gene deletion resulted in total elimination of both the higher and lower sensitivity components of the ion flux response to ACh. ACh-stimulated release from synaptosomes prepared from mice that were heterozygous for the null mutations (α4+/− and β2+/−) showed intermediate levels of ion flux. These results demonstrate that α4β2* nAChRs are responsible for both components of the ion flux response

Fig. 3

Potential subunit compositions of nAChRs expressed in dopaminergic nerve terminals. A combination of ligand binding ([3H]-epibatidine and [125I]-α-conotoxin MII), immunoprecipitation, and dopamine release data have led to the conclusion that rodent brain expresses a minimum of five different nAChR subtypes. Three of these (the two forms of α4β2 and α4α5β2) do not bind α-conotoxin MII with high affinity (α-conotoxin MII-resistant). The three a6-containing subtypes bind α-conotoxin MII with high affinity (conotoxin MII-sensitive). In general, the conotoxin-sensitive nAChR subtypes are activated by lower concentrations of agonist than are required to activate the α-conotoxin MII-resistant subtypes (Salminen et al. 2007)

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The road to discovery of neuronal nicotinic cholinergic receptor subtypes - PubMed (original) (raw)