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Molecular Pharmacology

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Research ArticleArticle

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

Steven Broadbent, Paul J. Groot-Kormelink, Paraskevi A. Krashia, Patricia C. Harkness, Neil S. Millar, Marco Beato and Lucia G. Sivilotti
Molecular Pharmacology October 2006, 70 (4) 1350-1357; DOI: https://doi.org/10.1124/mol.106.026682
Steven Broadbent
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Paul J. Groot-Kormelink
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Paraskevi A. Krashia
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Patricia C. Harkness
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Neil S. Millar
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Marco Beato
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Lucia G. Sivilotti
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Abstract

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 α3 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 α7 homomers or α/β pairs (α2, α3, α4, or α6 together with β2 or β4) produced robust nicotinic currents for all combinations, save α6β2 and α6β4. Coexpression of wild-type β3 led to a nearly complete loss of function (measured as maximum current response to acetylcholine) for α7 and for all functional α/β pairs except for α3β4. This effect was also seen in hippocampal neurons in culture, which lost their robust α7-like responses when transfected with β3. The level of surface expression of nicotinic binding sites (α3β4, α4β2, and α7) 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 α3β4 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.

Footnotes

  • This work was supported by the Wellcome Trust (project grants 064652 to L.G.S. and 074041 to N.S.M.) and by the Medical Research Council (PhD Studentship to S.B. and Training Fellowship to M.B.).

  • ABBREVIATIONS: nAChR, nicotinic acetylcholine receptor; ACh, acetylcholine; Popen, channel open probability; CNS, central nervous system; ANOVA, analysis of variance; MLA, methyllycaconitine.

  • ↵1 Current affiliation: Novartis Horsham Research Centre, Horsham, United Kingdom.

    • Received May 16, 2006.
    • Accepted July 5, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 70 (4)
Molecular Pharmacology
Vol. 70, Issue 4
1 Oct 2006
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Research ArticleArticle

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

Steven Broadbent, Paul J. Groot-Kormelink, Paraskevi A. Krashia, Patricia C. Harkness, Neil S. Millar, Marco Beato and Lucia G. Sivilotti
Molecular Pharmacology October 1, 2006, 70 (4) 1350-1357; DOI: https://doi.org/10.1124/mol.106.026682

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Research ArticleArticle

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

Steven Broadbent, Paul J. Groot-Kormelink, Paraskevi A. Krashia, Patricia C. Harkness, Neil S. Millar, Marco Beato and Lucia G. Sivilotti
Molecular Pharmacology October 1, 2006, 70 (4) 1350-1357; DOI: https://doi.org/10.1124/mol.106.026682
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