Published online before print October 18, 2001, doi: 10.1161/hh2301.100250
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Submitted on November 27, 2000
Revised on October 4, 2001
Accepted on October 4, 2001
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; Institute 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.
* To whom correspondence should be addressed. 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 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 calcium release channel
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