© 2000 American Heart Association, Inc.
Cellular Biology |
Ignition of Calcium Sparks in Arterial and Cardiac Muscle Through Caveolae
From the Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine, Charité University Hospitals, Humboldt University of Berlin, Germany, and Medical School Hannover, Department of Nephrology, Hannover, Germany.
Correspondence to Maik Gollasch, MD, PhD, Franz Volhard Clinic, Wiltbergstrasse 50, 13125 Berlin, Germany. E-mail gollasch{at}fvk-berlin.de
Abstract—Ca2+ sparks are localized intracellular Ca2+ events released through ryanodine receptors (RyRs) that control excitation-contraction coupling in heart and smooth muscle. Ca2+ spark triggering depends on precise delivery of Ca2+ ions through dihydropyridine (DHP)-sensitive Ca2+ channels to RyRs of the sarcoplasmic reticulum (SR), a process requiring a very precise alignment of surface and SR membranes containing Ca2+ influx channels and RyRs. Because caveolae contain DHP-sensitive Ca2+ channels and may colocalize with SR, we tested the hypothesis that caveolae are the structural element necessary for the generation of Ca2+ sparks. Using methyl-ß-cyclodextrin (dextrin) to deplete caveolae, we found that dextrin dose-dependently decreased the frequency, amplitude, and spatial size of Ca2+ sparks in arterial smooth muscle cells and neonatal cardiomyocytes. However, temporal characteristics of Ca2+ sparks were not significantly affected. We ruled out the possibility that the decreases in Ca2+ spark frequency and size are caused by changes in DHP-sensitive L-type channels, SR Ca2+ load, or changes in membrane potential. Our results suggest a novel signaling model that explains the formation of Ca2+ sparks in a caveolae microdomain. The transient elevation in [Ca2+]i at the inner mouth of a single caveolemmal Ca2+ channel induces simultaneous activation and thus opens several RyRs to generate a local Ca2+ release event, a Ca2+ spark. Alterations in the molecular assembly and ultrastructure of caveolae may lead to pathophysiological changes in Ca2+ signaling. Thus, caveolae may be intimately involved in cardiovascular cell dysfunction and disease.
Key Words: caveolae • arterial tone • excitation-contraction coupling • ryanodine receptor • L-type calcium channel
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