Published online before print October 18, 2001, doi: 10.1161/hh2301.100250
© 2001 American Heart Association, Inc.
Cellular Biology |
Regulation of Calcium Sparks and Spontaneous Transient Outward Currents by RyR3 in Arterial Vascular Smooth Muscle Cells
From HELIOS Klinikum-Berlin, Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine (M.L., M.F., M.W., F.C.L., M.G.), Medical Faculty of the Charité, Humboldt University Berlin; Department of Pathophysiology (W.J.), University of Vienna Medical School, Austria; DIBIT Scientific Insitute San Raffaele, Milan, Italy and Molecular Medicine Section (V.S.), Department of Neuroscience, University of Sienna, Italy; and Hannover Medical School, Department of Nephrology (H.H.), Hannover, Germany.
Correspondence to Maik Gollasch, MD, PhD, Franz Volhard Clinic, Humboldt University of Berlin, Wiltbergstrasse 50, D-13125 Berlin, Germany. E-mail gollasch{at}fvk-berlin.de
Intracellular Ca2+ levels control both contraction and relaxation in vascular smooth muscle cells (VSMCs). Ca2+-dependent relaxation is mediated by discretely localized Ca2+ release events through ryanodine receptor (RyR) channels in the sarcoplasmic reticulum (SR). These local increases in Ca2+ concentration, termed sparks, stimulate nearby Ca2+-activated K+ (BK) channels causing BK currents (spontaneous transient outward currents or STOCs). STOCs are hyperpolarizing currents that oppose vasoconstriction. Several RyR isoforms are coexpressed in VSMCs; however, their role in Ca2+ spark generation is unknown. To provide molecular information on RyR cluster function and assembly, we examined Ca2+ sparks and STOCs in RyR3-deficient freshly isolated myocytes of resistance-sized cerebral arteries from knockout mice and compared them to Ca2+ sparks in cells from wild-type mice. We used RT-PCR to identify RyR1, RyR2, and RyR3 mRNA in cerebral arteries. Ca2+ sparks in RyR3-deficient cells were similar in peak amplitude (measured as F/F0), width at half-maximal amplitude, and duration compared with wild-type cell Ca2+ sparks. However, the frequency of STOCs (between -60 mV and -20 mV) was significantly higher in RyR3-deficient cells than in wild-type cells. Ca2+ sparks and STOCs in both RyR3-deficient and wild-type cells were inhibited by ryanodine (10 µmol/L), external Ca2+ removal, and depletion of SR Ca2+ stores by caffeine (1 mmol/L). Isolated, pressurized cerebral arteries of RyR3-deficient mice developed reduced myogenic tone. Our results suggest that RyR3 is part of the SR Ca2+ spark release unit and plays a specific molecular role in the regulation of STOCs frequency in mouse cerebral artery VSMCs after decreased arterial tone.
Key Words: potassium currents • membrane potentials • caveolae • sarcoplasmic reticulum • ryanodine receptor
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