The diversity of subunit composition in nAChRs: Evolutionary origins, physiologic and pharmacologic consequences

Abstract

Nicotinic acetylcholine receptors are made up of homologous subunits, which are encoded by a large multigene family. The wide number of receptor oligomers generated display variable pharmacological properties. One of the main questions underlying research in molecular pharmacology resides in the actual role of this diversity. It is generally assumed that the observed differences between the pharmacology of homologous receptors, for instance, the EC 50 for the endogenous agonist, or the kinetics of desensitization, bear some kind of physiologic relevance in vivo. Here we develop the quite challenging point of view that, at least within a given subfamily of nicotinic receptor subunits, the pharmacologic variability observed in vitro would not be directly relevant to the function of receptor proteins in vivo. In vivo responses are not expected to be sensitive to mild differences in affinities, and several examples of functional replacement of one subunit by another have been unravelled by knockout animals. The diversity of subunits might have been conserved through evolution primarily to account for the topologic diversity of subunit distribution patterns, at the cellular and subcellular levels. A quantitative variation of pharmacological properties would be tolerated within a physiologic envelope, as a consequence of a near-neutral genetic drift. Such a "gratuitous" pharmacologic diversity is nevertheless of practical interest for the design of drugs, which would specifically tackle particular receptor oligomers with a defined subunit composition among the multiple nicotinic receptors present in the organism.

Tryptophan-scanning Mutagenesis in the αM3 Transmembrane Domain of the Muscle-type Acetylcholine Receptor

“…Data acquisition was conducted through the Clampex 9.2 program (Axon Instruments). Dose-response curves were generated from macroscopic peak currents (I) obtained from 7 different ACh concentrations (1,3,10,30,55,100, and 300 M ACh). Dose-response curves were fitted through the sigmoidal dose-response equation with variable slope using the GraphPad Prism 4 program (GraphPad),…”

“…The acetylcholine receptor (AChR) 2 belongs to the superfamily of the ligand-gated ion channel receptors that are of fundamental importance in the chemical synaptic transmission throughout the nervous system (1)(2)(3)(4). Defects in the AChR function could affect the transmission of nerve signals across synapses and cause pathological diseases such as the congenital myasthenic syndromes (5).…”

Potentiation of α7 nicotinic acetylcholine receptors via an allosteric transmembrane site

“…Although most nAChR subunits assemble only into heteromeric nAChRs (9,10), the ␣7 and ␣8 subunits are important exceptions. Both ␣7 and ␣8 are able to generate functional homomeric nAChRs (11,12) and have much closer sequence similarity to each other than to other nAChR subunits (2,9).…”

Molecular basis of the selective binding of MDMA enantiomers to the alpha4beta2 nicotinic receptor subtype: Synthesis, pharmacological evaluation and mechanistic studies

“…Previous studies have indicated that the nicotinic binding site is located at the centre of the extracellular domain of the receptor and lies at the interface between  and β subunits, which are known as the principal (P) and complementary (C) components, respectively [48][49][50]. Several residue stretches referred to as loops A, B and C in the  subunit, and D, E and F in the β subunit shape the binding site (in the following the symbols "" and "β" will be used before the residue to indicate the subunit it belongs to, and the numbering refers to the 4 and β2 subunits in rat).…”

“…To address the binding of MDMA to the 42 receptor, the homology model of the extracellular domains of the neuronal rat (4) 2 (2) 3 nAChR subtype constructed by Le Novère et al was used (PDB ID: 1OLE) [49]. The 3D model was refined with the software MOE 2008.10.…”