Ignition of Calcium Sparks in Arterial and Cardiac Muscle Through Caveolae

Ca sparks are localized intracellular Ca events released through ryanodine receptors (RyRs) that control excitation-contraction coupling in heart and smooth muscle. Ca spark triggering depends on precise delivery of Ca ions through dihydropyridine (DHP)-sensitive Ca channels to RyRs of the sarcoplasmic reticulum (SR), a process requiring a very precise alignment of surface and SR membranes containing Ca influx channels and RyRs. Because caveolae contain DHP-sensitive Ca channels and may colocalize with SR, we tested the hypothesis that caveolae are the structural element necessary for the generation of Ca sparks. Using methyl-β-cyclodextrin (dextrin) to deplete caveolae, we found that dextrin dose-dependently decreased the frequency, amplitude, and spatial size of Ca sparks in arterial smooth muscle cells and neonatal cardiomyocytes. However, temporal characteristics of Ca sparks were not significantly affected. We ruled out the possibility that the decreases in Ca spark frequency and size are caused by changes in DHP-sensitive L-type channels, SR Ca load, or changes in membrane potential. Our results suggest a novel signaling model that explains the formation of Ca sparks in a caveolae microdomain. The transient elevation in [Ca]i at the inner mouth of a single caveolemmal Ca channel induces simultaneous activation and thus opens several RyRs to generate a local Ca release event, a Ca spark. Alterations in the molecular assembly and ultrastructure of caveolae may lead to pathophysiological changes in Ca signaling. Thus, caveolae may be intimately involved in cardiovascular cell dysfunction and disease.