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(Circulation Research. 2001;88:63.)
© 2001 American Heart Association, Inc.

Cellular Biology

Ras Reduces L-Type Calcium Channel Current in Cardiac Myocytes

Corrective Effects of L-Channels and SERCA2 on [Ca²⁺]_i Regulation and Cell Morphology

Peter D. Ho, Jing-Song Fan, Nicole L. Hayes, Nehad Saada, Philip T. Palade, Christopher C. Glembotski, Patrick M. McDonough

From the SDSU Heart Institute and Department of Biology, San Diego State University (P.D.H., N.L.H., C.C.G., P.M.M.), San Diego, Calif, and Department of Physiology & Biophysics, University of Texas Medical Branch (J.-S.F., N.S., P.T.P.), Galveston, Tex.

Correspondence to Patrick M. McDonough, PhD, SDSU Heart Institute and Department of Biology, San Diego State University, 5500 Campanile Dr, San Diego, CA 92182. E-mail pmcdonough{at}biology.sdsu.edu

Abstract—Heart failure is associated with dysregulation of intracellular calcium ([Ca²⁺]_i), reduction in myofibrils, and increased activation of Ras, a regulator of signal-transduction pathways. To evaluate the potential effects of Ras on [Ca²⁺]_i, we expressed constitutively active Ras (Ha-Ras^V12) in cardiac myocytes and monitored [Ca²⁺]_i via fluorescence and electrophysiological techniques. Ha-Ras^V12 reduced the magnitude of the contractile calcium transients. Unexpectedly, however, calcium loading of the sarcoplasmic reticulum was increased, suggesting that Ha-Ras^V12 introduces a defect in excitation-calcium release coupling. Consistent with this idea, L-channel calcium currents were reduced by Ha-Ras^V12, which also downregulated the activity of the L-channel gene promoter. Coexpression of L-channels and SERCA2 largely corrected Ha-Ras^V12–induced dysregulation of [Ca²⁺]_i. Furthermore, whereas Ha-Ras^V12 downregulated myofibrils, this effect was blocked by coexpression of L-channels. These results suggest that Ras downregulates L-channel expression, which may play a pathophysiological role in cardiac disease.

Key Words: Ras • cardiac hypertrophy • SERCA2 • L-type calcium channel

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