Involvement of the α3 Subunit in Central Nicotinic Binding Populations

By P. Whiteaker, Cyrus G. Peterson, W. Xu, J. McIntosh, R. Paylor, A. Beaudet, A. C. Collins, M. Marks. Journal of Neuroscience, 2002

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The α3 subunit gene was one of the first neuronal nicotinic acetylcholine receptor (nAChR) subunits to be cloned (Boulter et al., 1986), but direct evidence of α3 subunit contributions to mammalian central nAChR populations has not been presented. The studies reported here used mice engineered to contain a null mutation in the α3 nAChR subunit gene (Xu et al., 1999) to examine the involvement of the α3 subunit in central nAChR populations. Heterologously expressed α3β2 and α3β4 nAChRs are pharmacologically similar to native [125I]α-conotoxin MII (α-CtxMII)-binding and 3-(2(S)-azetidinylmethoxy)pyridine dihydrochloride (A85380)-resistant [125I]epibatidine-binding nAChR subtypes, respectively. The hypothesis that both native sites are α3-subtype nAChRs was tested using quantitative autoradiography in α3-null mutant mice. Somewhat surprisingly, deletion of the α3 nAChR subunit gene did not affect expression of the great majority of [125I]α-CtxMII-binding sites, indicating that they do not correspond to heterologously expressed α3β2 nAChRs. The only exception to this was observed in the habenulointerpeduncular tract, where α3-dependent [125I]α-CtxMII binding was observed. This finding may suggest the presence of an additional, minor nicotinic population in this pathway. In contrast, most A85380-resistant [125I]epibatidine-binding nAChRs were dependent on α3 gene expression, suggesting that they do indeed correspond to an α3 nAChR subtype. However, widespread but lower levels of α3-independent A85380-resistant [125I]epibatidine binding were also seen. Again, this may indicate the existence of an additional, minor population of non-α3 A85380-resistant sites.

Subfields: Insect Science, Molecular Biology

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Neuronal nicotinic receptors: from structure to pathology. (2004, background): “Quantitative autoradiography studies of the brains of a3 Ko mice (Whiteaker et al., 2002) have shown that, unlike what was thought on the basis of the results of expression studies in heterologous systems (Cartier et al.”