Calcium Entry, Calcium Redistribution, and Exocytosis

A bstract : At a given cytosolic domain of a chromaffin cell, the rate and amplitude of the Ca 2+ concentration, [Ca 2+ ] c , depend on at least three efficient regulatory mechanisms: (1) the plasmalemmal Ca 2+ channels; (2) the endoplasmic reticulum (ER); and (3) the mitochondria. High‐voltage activated Ca 2+ channels of the L, N, P/Q, and R subtypes are expressed with different densities in various mammalian species; they are regulated by G proteins coupled to purinergic and opiate receptors, as well as by voltage and the local changes of [Ca 2+ ] c . Targeted aequorin and confocal microscopy show that Ca 2+ entry through Ca 2+ channels can refill the ER to near millimolar concentrations and causes the release of ER Ca 2+ (CICR). We have also seen that, depending on its degree of filling, the ER may act as a sink or source of Ca 2+ that modulates the release of catecholamine. Targeted aequorins with different Ca 2+ affinities show that mitochondria undergo surprisingly rapid millimolar Ca 2+ transients ([Ca 2+ ] M ) upon stimulation of chromaffin cells with ACh, high K + , or caffeine. Physiological stimuli generate [Ca 2+ ] c microdomains at these functional complexes in which the local subplasmalemmal [Ca 2+ ] c rises abruptly from 0.1 μM to about 50 μM. This triggers CICR, mitochondrial Ca 2+ uptake, and exocytosis in nearby secretory active sites. That this is true is shown by the observation that protonophores abolish mitochondrial Ca 2+ uptake and drastically increase catecholamine release by 3‐ to 5‐fold. This increase is likely due to acceleration of vesicle transport from a reserve pool to a ready‐release vesicle pool; such transport might be controlled by Ca 2+ redistribution to the cytoskeleton, through CICR and/or mitochondrial Ca 2+ release.