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(Circulation Research. 2007;101:69.)
© 2007 American Heart Association, Inc.

Cellular Biology

Dominant Negative Suppression of Rad Leads to QT Prolongation and Causes Ventricular Arrhythmias via Modulation of L-type Ca²⁺ Channels in the Heart

Hirotaka Yada, Mitsushige Murata, Kouji Shimoda, Shinsuke Yuasa, Haruko Kawaguchi, Masaki Ieda, Takeshi Adachi, Mitsuru Murata, Satoshi Ogawa, Keiichi Fukuda

From the Cardiopulmonary Division (H.Y., S.Y., M.I., S.O.), Department of Laboratory Medicine (Mitsushige M., Mitsuru M.), Animal Laboratory Center (K.S.), Department of Regenerative Medicine and Advanced Cardiac Therapeutics (H.K., K.F.), and Department of Biochemistry and Integrative Medical Biology (T.A.), School of Medicine, Keio University, Tokyo, Japan.

Correspondence to Mitsushige Murata, MD, PhD, Department of Laboratory Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail muratam{at}cpnet.med.keio.ac.jp

Disorders of L-type Ca²⁺ channels can cause severe cardiac arrhythmias. A subclass of small GTP-binding proteins, the RGK family, regulates L-type Ca²⁺ current (I_Ca,L) in heterologous expression systems. Among these proteins, Rad (Ras associated with diabetes) is highly expressed in the heart, although its role in the heart remains unknown. Here we show that overexpression of dominant negative mutant Rad (S105N) led to an increase in I_Ca,L and action potential prolongation via upregulation of L-type Ca²⁺ channel expression in the plasma membrane of guinea pig ventricular cardiomyocytes. To verify the in vivo physiological role of Rad in the heart, a mouse model of cardiac-specific Rad suppression was created by overexpressing S105N Rad, using the -myosin heavy chain promoter. Microelectrode studies revealed that action potential duration was significantly prolonged with visible identification of a small plateau phase in S105N Rad transgenic mice, when compared with wild-type littermate mice. Telemetric electrocardiograms on unrestrained mice revealed that S105N Rad transgenic mice had significant QT prolongation and diverse arrhythmias such as sinus node dysfunction, atrioventricular block, and ventricular extrasystoles, whereas no arrhythmias were observed in wild-type mice. Furthermore, administration of epinephrine induced frequent ventricular extrasystoles and ventricular tachycardia in S105N Rad transgenic mice. This study provides novel evidence that the suppression of Rad activity in the heart can induce ventricular tachycardia, suggesting that the Rad-associated signaling pathway may play a role in arrhythmogenesis in diverse cardiac diseases.

Key Words: G protein • L-type Ca²⁺ channels • arrhythmia

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