Ca2+ signaling in smooth muscle: TRPC6, NCX,and LNats in nanodomains

Following the recent observation of localized cytosolic subplasmalemmal Na⁺] elevations (LNats) in rat aortic smooth muscle cells, we discuss here the current evidence for the structural and molecular roles of cytosolic nanodomains at close junctions of the plasma membrane (PM) and sarcoplasmic reticulum (SR) in the generation of LNats. These junctions, the loss of which might contribute to vascular aging and disease, provide a platform for ion metabolism signalplexes and the interaction of localized Na⁺ and Ca²⁺ gradients. We moreover suggest the existence in the junctions of a Na⁺ diffusional barrier as a necessary condition for the generation of LNats. LNats are likely a fundamental feature of near membrane ion signaling in many cell types, and their discovery offers new possibilities for elucidating the mechanism, function and pathogenesis of Na⁺ and Ca²⁺ signaling nanodomains.