Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Biol Chem
2012 Jun 29;28727:22749-58. doi: 10.1074/jbc.M111.291872.
Show Gene links
Show Anatomy links
Molecular determinants of Gem protein inhibition of P/Q-type Ca2+ channels.
Fan M, Zhang WK, Buraei Z, Yang J.
???displayArticle.abstract???
The RGK family of monomeric GTP-binding proteins potently inhibits high voltage-activated Ca(2+) channels. The molecular mechanisms of this inhibition are largely unclear. In Xenopus oocytes, Gem suppresses the activity of P/Q-type Ca(2+) channels on the plasma membrane. This is presumed to occur through direct interactions of one or more Gem inhibitory sites and the pore-forming Ca(v)2.1 subunit in a manner dependent on the Ca(2+) channel subunit β (Ca(v)β). In this study we investigated the molecular determinants in Gem that are critical for this inhibition. Like other RGK proteins, Gem contains a conserved Ras-like core and extended N and C termini. A 12-amino acid fragment in the C terminus was found to be crucial for and sufficient to produce Ca(v)β-dependent inhibition, suggesting that this region forms an inhibitory site. A three-amino acid motif in the core was also found to be critical, possibly forming another inhibitory site. Mutating either site individually did not hamper Gem inhibition, but mutating both sites together completely abolished Gem inhibition without affecting Gem protein expression level or disrupting Gem interaction with Ca(v)2.1 or Ca(v)β. Mutating Gem residues that are crucial for interactions with previously demonstrated RGK modulators such as calmodulin, 14-3-3, and phosphatidylinositol lipids did not significantly affect Gem inhibition. These results suggest that Gem contains two candidate inhibitory sites, each capable of producing full inhibition of P/Q-type Ca(2+) channels.
Béguin,
Roles of 14-3-3 and calmodulin binding in subcellular localization and function of the small G-protein Rem2.
2005, Pubmed
Béguin,
Roles of 14-3-3 and calmodulin binding in subcellular localization and function of the small G-protein Rem2.
2005,
Pubmed Béguin,
Regulation of Ca2+ channel expression at the cell surface by the small G-protein kir/Gem.
2001,
Pubmed
,
Xenbase Béguin,
RGK small GTP-binding proteins interact with the nucleotide kinase domain of Ca2+-channel beta-subunits via an uncommon effector binding domain.
2007,
Pubmed Béguin,
Nuclear sequestration of beta-subunits by Rad and Rem is controlled by 14-3-3 and calmodulin and reveals a novel mechanism for Ca2+ channel regulation.
2006,
Pubmed Béguin,
14-3-3 and calmodulin control subcellular distribution of Kir/Gem and its regulation of cell shape and calcium channel activity.
2005,
Pubmed Buraei,
The ß subunit of voltage-gated Ca2+ channels.
2010,
Pubmed Catterall,
Structure and regulation of voltage-gated Ca2+ channels.
2000,
Pubmed Chen,
Expression of Rem2, an RGK family small GTPase, reduces N-type calcium current without affecting channel surface density.
2005,
Pubmed Correll,
Analysis of the Rem2 - voltage dependant calcium channel beta subunit interaction and Rem2 interaction with phosphorylated phosphatidylinositide lipids.
2008,
Pubmed Correll,
Plasma membrane targeting is essential for Rem-mediated Ca2+ channel inhibition.
2007,
Pubmed Correll,
The RGK family of GTP-binding proteins: regulators of voltage-dependent calcium channels and cytoskeleton remodeling.
2008,
Pubmed Fan,
Direct inhibition of P/Q-type voltage-gated Ca2+ channels by Gem does not require a direct Gem/Cavbeta interaction.
2010,
Pubmed
,
Xenbase Felix,
Molecular regulation of voltage-gated Ca2+ channels.
2005,
Pubmed Finlin,
Regulation of L-type Ca2+ channel activity and insulin secretion by the Rem2 GTPase.
2005,
Pubmed Finlin,
Phosphorylation-dependent association of the Ras-related GTP-binding protein Rem with 14-3-3 proteins.
1999,
Pubmed Finlin,
Regulation of voltage-gated calcium channel activity by the Rem and Rad GTPases.
2003,
Pubmed Finlin,
Analysis of the complex between Ca2+ channel beta-subunit and the Rem GTPase.
2006,
Pubmed Fischer,
Calmodulin binds to and inhibits GTP binding of the ras-like GTPase Kir/Gem.
1996,
Pubmed Flynn,
Regulation of calcium channels by RGK proteins.
2010,
Pubmed Flynn,
Molecular determinants of Rem2 regulation of N-type calcium channels.
2008,
Pubmed Kelly,
The RGK family: a regulatory tail of small GTP-binding proteins.
2005,
Pubmed Leyris,
RGK GTPase-dependent CaV2.1 Ca2+ channel inhibition is independent of CaVbeta-subunit-induced current potentiation.
2009,
Pubmed
,
Xenbase Mahalakshmi,
Nuclear localization of endogenous RGK proteins and modulation of cell shape remodeling by regulated nuclear transport.
2007,
Pubmed Mahalakshmi,
Nuclear transport of Kir/Gem requires specific signals and importin alpha5 and is regulated by calmodulin and predicted serine phosphorylations.
2007,
Pubmed Moyers,
Rad and Rad-related GTPases interact with calmodulin and calmodulin-dependent protein kinase II.
1997,
Pubmed Pang,
Rem GTPase interacts with the proximal CaV1.2 C-terminus and modulates calcium-dependent channel inactivation.
2010,
Pubmed Sasaki,
Direct inhibition of the interaction between alpha-interaction domain and beta-interaction domain of voltage-dependent Ca2+ channels by Gem.
2005,
Pubmed Seu,
Dose-dependent and isoform-specific modulation of Ca2+ channels by RGK GTPases.
2006,
Pubmed
,
Xenbase Splingard,
Biochemical and structural characterization of the gem GTPase.
2007,
Pubmed Ward,
Phosphorylation of critical serine residues in Gem separates cytoskeletal reorganization from down-regulation of calcium channel activity.
2004,
Pubmed Xu,
Molecular mechanisms, and selective pharmacological rescue, of Rem-inhibited CaV1.2 channels in heart.
2010,
Pubmed Yada,
Dominant negative suppression of Rad leads to QT prolongation and causes ventricular arrhythmias via modulation of L-type Ca2+ channels in the heart.
2007,
Pubmed Yang,
Rem, a member of the RGK GTPases, inhibits recombinant CaV1.2 channels using multiple mechanisms that require distinct conformations of the GTPase.
2010,
Pubmed Yang,
Genetically encoded molecules for inducibly inactivating CaV channels.
2007,
Pubmed Yanuar,
Crystal structure of human Rad GTPase of the RGK-family.
2006,
Pubmed
