TY - JOUR
T1 - Ras reduces L-type calcium channel current in cardiac myocytes
T2 - Corrective effects of L-channels and SERCA2 on [Ca2+]i regulation and cell morphology
AU - Ho, Peter D.
AU - Fan, Jing Song
AU - Hayes, Nicole L.
AU - Saada, Nehad
AU - Palade, Philip T.
AU - Glembotski, Christopher C.
AU - McDonough, Patrick M.
N1 - Funding Information:
Manuscript received August 1, 2003; revised November 25, 2003. This work was supported by IITA, Korea. This paper was recommended by Associate Editor K. Parhi. Y. Jiang is with the Department of Electrical and Computer Engineering, University of Nevada, Las Vegas, NV 89154 USA. A. Al-Sheraidah, Y. Wang, and E. Sha are with the Department of Computer Science, Erik Jonsson School of Engineering and Computer Science, University of Texas at Dallas, Richardson, TX 75083-0688 USA (e-mail: [email protected]). J.-G. Chung is with the Division of Electronic and Information Engineering, Chonbuk National University, Chonju 561-756, South Korea. Digital Object Identifier 10.1109/TCSII.2004.831429
PY - 2001/1/19
Y1 - 2001/1/19
N2 - 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-RasV12) in cardiac myocytes and monitored [Ca2+]i via fluorescence and electrophysiological techniques. Ha-RasV12 reduced the magnitude of the contractile calcium transients. Unexpectedly, however, calcium loading of the sarcoplasmic reticulum was increased, suggesting that Ha-RasV12 introduces a defect in excitation-calcium release coupling. Consistent with this idea, L-channel calcium currents were reduced by Ha-RasV12, which also downregulated the activity of the L-channel gene promoter. Coexpression of L-channels and SERCA2 largely corrected Ha-RasV12-induced dysregulation of [Ca2+]i. Furthermore, whereas Ha-RasV12 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.
AB - 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-RasV12) in cardiac myocytes and monitored [Ca2+]i via fluorescence and electrophysiological techniques. Ha-RasV12 reduced the magnitude of the contractile calcium transients. Unexpectedly, however, calcium loading of the sarcoplasmic reticulum was increased, suggesting that Ha-RasV12 introduces a defect in excitation-calcium release coupling. Consistent with this idea, L-channel calcium currents were reduced by Ha-RasV12, which also downregulated the activity of the L-channel gene promoter. Coexpression of L-channels and SERCA2 largely corrected Ha-RasV12-induced dysregulation of [Ca2+]i. Furthermore, whereas Ha-RasV12 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.
KW - Cardiac hypertrophy
KW - L-type calcium channel
KW - Ras
KW - SERCA2
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U2 - 10.1161/01.RES.88.1.63
DO - 10.1161/01.RES.88.1.63
M3 - Article
C2 - 11139475
AN - SCOPUS:0035910613
SN - 0009-7330
VL - 88
SP - 63
EP - 69
JO - Circulation research
JF - Circulation research
IS - 1
ER -