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| Title: | RECIPROCAL REGULATION OF RGS PROTEINS BY PHOSPHOLIPID AND CA2+/CALMODULIN IN CARDIOMYOCYTES: IMPLICATION FOR CHOLINERGIC REGULATION OF HEART RATES | |
| DOI No: | 10.1142/9789812702234_0008 | |
| Source: | ADVANCES IN ELECTROCARDIOLOGY 2004 (pp 50-53) | |
| Author(s): | MASARU ISHII
Department of Pharmacology, Osaka University Graduate School of Medicine, Suita, Japan Kobe Biotechnology Center for Biological Simulations, Kobe University, Kobe, Japan YOSHIHISA KURACHI Department of Pharmacology, Osaka University Graduate School of Medicine, Suita, Japan Kobe Biotechnology Center for Biological Simulations, Kobe University, Kobe, Japan |
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| Abstract: | G-protein-gated potassium (KG) channels, which are directly activated by G-protein βy subunits released from pertussis toxin-sensitive G-proteins, exist on atrial myocytes, and are responsible for acetylcholine (ACh)-induced deceleration of heart beats. A characteristic gating property of native KG currents is time-dependent current increase during hyperpolarizing pulses, named "relaxation". We have previously shown that this relaxation gating is apparent voltage-dependent control of trimeric G-protein cycle by a family of proteins, designated 'regulators of G-protein-signaling (RGS)' proteins. The voltage-dependent formation of Ca2+/calmodulin (CaM) facilitated the GTPase-accelerating activity of the RGS protein by removing intrinsic inhibition mediated by a kind of phospholipid, phosphatidylinositol-3,4,5,-trisphosphate (PI(3,4,5)P3). Here we show the molecular mechanism of this reciprocal control of RGS-action. We detected the specific interaction between RGS4 and PI(3,4,5)P3, which was abolished by Ca2+/CaM. This modulation exclusively occurred within RGS domain, which is responsible for GTPase-accelerating activity. We identified the cluster of positively charged residues in RGS domain, which lie just behind the residues crucial for RGS-Ga interaction, as a candidate of the molecular switch of PI(3,4,5)P3-modulation. Because these residues are conserved in almost all RGS protein subtypes expressed in cardiac myocytes, this allosteric modulation of RGS proteins should be important in the physiological control of G-protein mediated cell signalings in the heart. Their possible roles in adrenergic- and cholinergic- regulation of cardiac functions are discussed. | |
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