RGS (regulators of G-protein signalling) are a diverse group of proteins, which accelerate intrinsic GTP hydrolysis on heterotrimeric G-protein α subunits. They are involved in the control of a physiological behaviour known as ‘relaxation’ of G-protein-gated K+ channels in cardiac myocytes. The GTPase-accelerating activity of cardiac RGS proteins, such as RGS4, is inhibited by PtdIns(3,4,5)P3 (phosphatidylinositol 3,4,5-trisphosphate) and this inhibition is cancelled by Ca2+/calmodulin (CaM) formed during membrane depolarization. G-protein-gated K+ channel activity decreases on depolarization owing to the facilitation of GTPase-activating protein activity by RGS proteins and vice versa on hyperpolarization. The molecular mechanism responsible for this reciprocal control of RGS action by PtdIns(3,4,5)P3 and Ca2+/CaM, however, has not been fully elucidated. Using lipid–protein co-sedimentation assay and surface plasmon resonance measurements, we show in the present study that the control of the GTPase-accelerating activity of the RGS4 protein is achieved through the competitive binding of PtdIns(3,4,5)P3 and Ca2+/CaM within its RGS domain. Competitive binding occurs exclusively within the RGS domain and involves a cluster of positively charged residues located on the surface opposite to the Gα interaction site. In the RGS proteins conserving these residues, the reciprocal regulation by PtdIns(3,4,5)P3 and Ca2+/CaM may be important for their physiological regulation of G-protein signalling.
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Research Article|
December 14 2004
Phosphatidylinositol 3,4,5-trisphosphate and Ca2+/calmodulin competitively bind to the regulators of G-protein-signalling (RGS) domain of RGS4 and reciprocally regulate its action
Masaru ISHII;
Masaru ISHII
1Department of Pharmacology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
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Satoru FUJITA;
Satoru FUJITA
1Department of Pharmacology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
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Mitsuhiko YAMADA;
Mitsuhiko YAMADA
1Department of Pharmacology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
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Yukio HOSAKA;
Yukio HOSAKA
1Department of Pharmacology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
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Yoshihisa KURACHI
Yoshihisa KURACHI
1
1Department of Pharmacology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
1To whom correspondence should be addressed (email ykurachi@pharma2.med.osaka-u.ac.jp).
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Publisher: Portland Press Ltd
Received:
March 11 2004
Revision Received:
July 26 2004
Accepted:
August 23 2004
Accepted Manuscript online:
August 23 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 385 (1): 65–73.
Article history
Received:
March 11 2004
Revision Received:
July 26 2004
Accepted:
August 23 2004
Accepted Manuscript online:
August 23 2004
Citation
Masaru ISHII, Satoru FUJITA, Mitsuhiko YAMADA, Yukio HOSAKA, Yoshihisa KURACHI; Phosphatidylinositol 3,4,5-trisphosphate and Ca2+/calmodulin competitively bind to the regulators of G-protein-signalling (RGS) domain of RGS4 and reciprocally regulate its action. Biochem J 1 January 2005; 385 (1): 65–73. doi: https://doi.org/10.1042/BJ20040404
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