QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.106.026682v1 70/4/1350    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Broadbent, S. Articles by Sivilotti, L. G. Search for Related Content PubMed PubMed Citation Articles by Broadbent, S. Articles by Sivilotti, L. G.

Incorporation of the β3 Subunit Has a Dominant-Negative Effect on the Function of Recombinant Central-Type Neuronal Nicotinic Receptors

Department of Pharmacology, University College London, London, United Kingdom

The β3 neuronal nicotinic subunit is localized in dopaminergic areas of the central nervous system, in which many other neuronal nicotinic subunits are expressed. So far, β3 has only been shown to form functional receptors when expressed together with the 3 and β4 subunits. We have systematically tested in Xenopus laevis oocytes the effects of coexpressing human β3 with every pairwise functional combination of neuronal nicotinic subunits likely to be relevant to the central nervous system. Expression of 7 homomers or /β pairs (2, 3, 4, or 6 together with β2 or β4) produced robust nicotinic currents for all combinations, save 6β2 and 6β4. Coexpression of wild-type β3 led to a nearly complete loss of function (measured as maximum current response to acetylcholine) for 7 and for all functional /β pairs except for 3β4. This effect was also seen in hippocampal neurons in culture, which lost their robust 7-like responses when transfected with β3. The level of surface expression of nicotinic binding sites (3β4, 4β2, and 7) in tsA201 cells was only marginally affected by β3 expression. Furthermore, the dominant-negative effect of β3 was abolished by a valine-serine mutation in the 9' position of the second transmembrane domain of β3, a mutation believed to facilitate channel gating. Our results show that incorporation of β3 into neuronal nicotinic receptors other than 3β4 has a powerful dominant-negative effect, probably due to impairment in gating. This raises the possibility of a novel regulatory role for the β3 subunit on neuronal nicotinic signaling in the central nervous system.

Address correspondence to: Dr. Lucia Sivilotti, Department of Pharmacology, University College London, Gower St., London, WC1E 6BT, UK. E-mail: l.sivilotti{at}ucl.ac.uk

This article has been cited by other articles:

				R. M. Drenan, R. Nashmi, P. Imoukhuede, H. Just, S. McKinney, and H. A. Lester Subcellular Trafficking, Pentameric Assembly, and Subunit Stoichiometry of Neuronal Nicotinic Acetylcholine Receptors Containing Fluorescently Labeled {alpha}6 and 3 Subunits Mol. Pharmacol., January 1, 2008; 73(1): 27 - 41. [Abstract] [Full Text] [PDF]

				L. Tapia, A. Kuryatov, and J. Lindstrom Ca2+ Permeability of the ({alpha}4)3(beta2)2 Stoichiometry Greatly Exceeds That of ({alpha}4)2(beta2)3 Human Acetylcholine Receptors Mol. Pharmacol., March 1, 2007; 71(3): 769 - 776. [Abstract] [Full Text] [PDF]