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

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

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Dresviannikov, Andriy V. Page, Karen M. Leroy, Jerôme Pratt, Wendy S. Dolphin, Annette C.
Description	Country affiliation: United kingdom Author Affiliation: Dresviannikov AV ( Laboratory of Cellular and Molecular Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.)
Abstract	CaVbeta 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 Gbetagamma-mediated inhibitory modulation of CaV2.2 channels did not require the interaction of a CaVbeta subunit with the CaValpha1 subunit, when such interaction was prevented by a mutation in the alpha1 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 CaVbeta subunits to support voltage-dependent G protein modulation in order to determine the minimal domain of the CaVbeta subunit that is required for this process. We have coexpressed the CaVbeta subunit constructs with CaV2.2 and alpha2delta-2, studied modulation by the activation of the dopamine D2 receptor, and also examined basal tonic modulation. Our main finding is that the CaVbeta subunit GK domains, from either beta1b or beta2, are sufficient to restore voltage dependence to G protein modulation. We also found that the removal of the variable HOOK region from beta2a promotes tonic voltage-dependent G protein modulation. We propose that the absence of the HOOK region enhances Gbetagamma binding affinity, leading to greater tonic modulation by basal levels of Gbetagamma. This tonic modulation requires the presence of an SH3 domain, as tonic modulation is not supported by any of the CaVbeta subunit GK domains alone.
File Format	HTM / HTML
ISSN	00316768
e-ISSN	14322013
DOI	10.1007/s00424-008-0549-7
Journal	Pflügers Archiv - European Journal of Physiology
Issue Number	4
Volume Number	457
Language	English
Publisher	Springer
Publisher Date	2009-02-01
Publisher Place	Germany
Access Restriction	Open
Subject Keyword	Discipline Physiology Calcium Channels Metabolism Gtp-binding Proteins Ion Channel Gating Physiology Protein Subunits Animals Genetics Patch-clamp Techniques Protein Structure, Tertiary Two-hybrid System Techniques Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Physiology Physiology (medical) Clinical Biochemistry

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