Intravesicular Factors Controlling Exocytosis in Chromaffin Cells

Abstract

Chromaffin granules are similar organelles to the large dense core vesicles (LDCV) present in many secretory cell types including neurons. LDCV accumulate solutes at high concentrations (catecholamines, 0.5-1 M; ATP, 120-300 mM; or Ca(2+), 40 mM (Bulenda and Gratzl Biochemistry 24:7760-7765, 1985). Solutes seem to aggregate to a condensed matrix to elude osmotic lysis. The affinity of solutes for LDCV matrix is responsible for the delayed release of catecholamines during exocytosis. The aggregation of solutes occurs due to a specific H(+) pump denominated V-ATPase that maintains an inner acidic media (pH ≈5.5). This pH gradient against cytosol is also responsible for the vesicular accumulation of amines and Ca(2+). When this gradient is reduced by modulation of the V-ATPase activity, catecholamines and Ca(2+) are moved toward the cytosol. In addition, some drugs largely accumulate inside LDCV and not only impair the accumulation of natural solutes, but also act as false neurotransmitters when they are co-released with catecholamines. There is much experimental evidence to conclude that the physiological modulation of vesicle pH and the manipulation of intravesicular media with drugs affect the LDCV cargo and change the kinetics of exocytosis. Here, we will present some experimental data demonstrating the participation of drugs in the kinetics of exocytosis through changes in the composition of vesicular media. We also offer a model to explain the regulation of exocytosis by the intravesicular media that conciliate the experimentally obtained data.

Low pHoboosts burst firing and catecholamine release by blocking TASK‐1 and BK channels while preserving Cav1 channels in mouse chromaffin cells

“…altered vesicle loading) (Borges et al . ), formation of the fusion pore and secretion of vesicle content (Lindau & Alvarez de Toledo, ) or alteration of bound CA in the vesicle matrix (Jankowski et al . ).…”

Mice overexpressing chromogranin A display hypergranulogenic adrenal glands with attenuated ATP levels contributing to the hypertensive phenotype

“…The increased exocytotic release of catecholamine in four-copy mice also expends ATP and this could result in the observed decreased levels of ATP [52]. ATP is the first component released from the DCVs and then is followed by release of all other vesicular constituents during exocytosis [53]. ATP, after its release into the extracellular environment, is degraded by ectonucleotidases into adenine and phosphate.…”

Amperometry methods for monitoring vesicular quantal size and regulation of exocytosis release

“…The concentration of neurotransmitters in vesicles of chromaffin cells from adrenal glands is estimated to about 0.5–1 M [ 2 , 32 , 47 , 62 ]. How the vesicle can perform this act and maintain charge neutrality and osmotic balance is still debated [ 19 , 31 , 35 , 56 ]. The quantal size can be tuned using pharmacology enhancing or blocking the passage of neurotransmitters by specific transporter protein into the vesicle compartment or by affecting the proton/electrical gradient across the vesicle membrane and consequently affect the amount of transmitters released into the synaptic cleft [ 30 , 51 , 58 , 74 ].…”