Ignition of calcium sparks in arterial and cardiac muscle through caveolae

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-beta -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.