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Determinants of the voltage dependence of G protein modulation within calcium channel β subunits

Dresviannikov, A.V.; Page, K.M.; Leroy, J.; Pratt, W.S.; Dolphin, A.C.; (2009) Determinants of the voltage dependence of G protein modulation within calcium channel β subunits. Pflügers Archiv - European Journal of Physiology , 457 (4) pp. 743-756. 10.1007/s00424-008-0549-7. Green open access

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CaVβ subunits of voltage-gated calcium channels contain two conserved domains, a src-homology-3 (SH3) domain and a guanylate kinase-like (GK) domain with an intervening HOOK domain. We have shown in a previous study that, although Gβγ-mediated inhibitory modulation of CaV2.2 channels did not require the interaction of a CaVβ subunit with the CaVα1 subunit, when such interaction was prevented by a mutation in the α1 subunit, G protein modulation could not be removed by a large depolarization and showed voltage-independent properties (Leroy et al., J Neurosci 25:6984–6996, 2005). In this study, we have investigated the ability of mutant and truncated CaVβ subunits to support voltage-dependent G protein modulation in order to determine the minimal domain of the CaVβ subunit that is required for this process. We have coexpressed the CaVβ subunit constructs with CaV2.2 and α2δ-2, studied modulation by the activation of the dopamine D2 receptor, and also examined basal tonic modulation. Our main finding is that the CaVβ subunit GK domains, from either β1b or β2, are sufficient to restore voltage dependence to G protein modulation. We also found that the removal of the variable HOOK region from β2a promotes tonic voltage-dependent G protein modulation. We propose that the absence of the HOOK region enhances Gβγ binding affinity, leading to greater tonic modulation by basal levels of Gβγ. This tonic modulation requires the presence of an SH3 domain, as tonic modulation is not supported by any of the CaVβ subunit GK domains alone.

Type: Article
Title: Determinants of the voltage dependence of G protein modulation within calcium channel β subunits
Open access status: An open access version is available from UCL Discovery
DOI: 10.1007/s00424-008-0549-7
Publisher version: http://dx.doi.org/10.1007/s00424-008-0549-7
Language: English
Additional information: © The Author(s) 2008. This article is published with open access at Springerlink.com The article is reproduced here under the terms of the Creative Commons Attribution Noncommercial License, which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited, please see http://creativecommons.org/licenses/by-nc/2.5
Keywords: Calcium channel, beta subunit, electrophysiology
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/20084
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