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(Circulation Research. 2001;89:1045.)
© 2001 American Heart Association, Inc.

Cellular Biology

Ca²⁺ Elevation Evoked by Membrane Depolarization Regulates G Protein Cycle via RGS Proteins in the Heart

Masaru Ishii, Atsushi Inanobe, Satoru Fujita, Yasunaka Makino, Yukio Hosoya, Yoshihisa Kurachi

From the Department of Pharmacology II (M.I., A.I., S.F., Y.M., Y.K.), Graduate School of Medicine, Osaka University, Suita, Osaka, and Department of Nursing (Y.H.), Yamagata School of Health Science, Yamagata, Japan.

Correspondence to Yoshihisa Kurachi, MD, PhD, Department of Pharmacology II, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail ykurachi{at}pharma2.med.osaka-u.ac.jp

Regulators of G protein signaling (RGS), which act as GTPase activators, are a family of cytosolic proteins emerging rapidly as an important means of controlling G protein-mediated cell signals. The importance of RGS action has been verified in vitro for various kinds of cell function. Their in situ modes of action in intact cells are, however, poorly understood. Here we show that an increase in intracellular Ca²⁺ evoked by membrane depolarization controls the RGS action on G protein activation of muscarinic K⁺ (K_G) channel in the heart. Acetylcholine-induced K_G current exhibits a slow time-dependent increase during hyperpolarizing voltage steps, referred to as "relaxation." This reflects the relief from the decrease in available K_G channel number induced by cell depolarization. This phenomenon is abolished when an increase in intracellular Ca²⁺ is prevented. It is also abolished when a calmodulin inhibitor or a mutant RGS4 is applied that can bind to calmodulin but that does not accelerate GTPase activity. Therefore, an increase in intracellular Ca²⁺ and the resultant formation of Ca²⁺/calmodulin facilitate GTPase activity of RGS and thus decrease the available channel number on depolarization. These results indicate a novel and probably general pathway that Ca²⁺-dependent signaling regulates the G protein cycle via RGS proteins.

Key Words: G protein-activated K⁺ channel • regulators of G protein signaling • Ca²⁺ • calmodulin • cell excitation

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