An Integral View on Calcium Channels and Transporters Shaping Calcium and Exocytotic Signals in Chromaffin Cells

Abstract

This chapter focuses on calcium movements and their impact on exocytosis in adrenal medullary chromaffin cells (CCs). Upon depolarization, Ca2+ enters the cell through open plasmalemmal voltage-dependent calcium channels (Cav channels) driven by a large electrochemical gradient. This gives rise to subplasmalemmal high-Ca2+ microdomains (HCMDs) near active exocytotic sites were a fraction of secretory catecholamine-storing chromaffin granules are docked, the so-called readily releasable vesicle pool (RRVP). These high transients of cytosolic Ca2+ concentrations ([Ca2+]c) are required for the fast exocytotic release of vesicle cargo to the extracellular space. The HCMD is cleared by three regulatory mechanisms, namely the binding of Ca2+ to calcium-binding proteins (CBPs), the rapid and efficient Ca2+ uptake into mitochondria through the mitochondrial calcium uniporter (MICU), and the uptake of Ca2+ into the endoplasmic reticulum (ER) through the sarcoendoplasmic reticulum ATPase (SERCA). The subsequent release of Ca2+ back into the cytosol from mitochondria, through the mitochondrial Na+/Ca2+ exchanger (MNCX) and from the ER via the inositol trisphosphate receptor (IP3R) and the ryanodine receptor (RyR), generates low-Ca2+ microdomains (LCMDs) at cytosolic sites. This lower [Ca2+]c is required for the transport of mature new chromaffin granules from a reserve vesicle pool (RVP) to the RRVP; this process serves to refill the RRVP with new vesicles and to secure new rounds of exocytosis. The Ca2+ efflux to the extracellular space through two calcium transporters (i.e., a Ca2+-ATPase or Ca2+ pump and the plasmalemmal Na+/Ca2+ exchanger (PNCX)), also participates in the regulation of exocytosis. Finally, an integrative picture of Ca2+ movements and the balance of Ca2+ in the context of exocytosis is drawn. The review ends with a corollary on the vast amount of knowledge accumulated during the last 60 years since Douglas and Rubin demonstrated the absolute requirement of Ca2+ for the secretion of catecholamines from the perfused cat adrenal gland, triggered by acetylcholine. A prediction on the evolution of the stimulus-secretion coupling process and its impact on stress and disease is finally made.