The coupling of plasma membrane calcium entry to calcium uptake by endoplasmic reticulum and mitochondria

Abstract

Cross-talk between organelles and plasma membrane Ca2+ channels is essential for modulation of the cytosolic Ca2+ ([Ca2+]C) signals, but such modulation may differ among cells. In chromaffin cells Ca2+ entry through voltage-operated channels induces calcium release from the endoplasmic reticulum (ER) that amplifies the signal. [Ca2+]C microdomains as high as 20–50 μM are sensed by subplasmalemmal mitochondria, which accumulate large amounts of Ca2+ through the mitochondrial Ca2+ uniporter (MCU). Mitochondria confine the high-Ca2+ microdomains (HCMDs) to beneath the plasma membrane,where exocytosis of secretory vesicles happens. Cell core [Ca2+]C is much smaller (1–2 μM). By acting as a Ca2+ sink, mitochondria stabilise theHCMDin space and time. In non-excitableHEK293 cells, activation of store-operated Ca2+ entry, triggered by ERCa2+ emptying, also generated subplasmalemmal HCMDs, but, in this case, most of the Ca2+ was taken up by the ER rather than bymitochondria. The smaller size of the [Ca2+]C peak in this case (about 2 μM)may contribute to this outcome, as the sarco-endoplasmic reticulum Ca2+ ATPase has much higher Ca2+ affinity than MCU. It is also possible that the relative positioning of organelles, channels and effectors, as well as cytoskeleton and accessory proteins plays an important role.