[Calcium-dependent regulated secretion is controlled by GTPase Rab3 in neuroendocrine cells]

Changes in intracellular free calcium concentration ([Ca2+]i) play a fundamental role in the regulation of hormone secretion by endocrine and neuronal cells. The increase in [Ca2+]i is one of the principle events in stimulus-secretion coupling. Secretory phenomena are subjected to modulation via a large number of intracellular factors which can act on vesicular transport, exocytosis or endocytosis. Among these factors are proteins able to bind and hydrolyse the nucleotide GTP belonging to the ras superfamily of small GTPases (or superfamily of small G proteins). GTPases of the Sec4/Ypt1/Rab family have been implicated in the regulation of intracellular vesicle traffic. A role for Rab3 in regulating secretion was initially proposed because of its specific expression in the nervous and endocrine systems, and its association with secretory vesicles. The function of Rab3 has been studied in two types of neuroendocrine cells: the anterior pituitary lactotroph cells and the adrenal medulla chromaffin cells. Two techniques were combined: intracellular injection of antisense oligonucleotides and recombinant proteins, followed by membrane capacitance measurements. The inhibition of Rab3b synthesis in lactotroph cells by antisense oligonucleotides provokes an inhibition of exocytosis. On the other hand, injection of antisense oligonucleotides directed against rab3a into chromaffin cells led to a stimulation of the secretory response to successive depolarizations of the cell membrane. These results indicate that Rab3 proteins control the calcium-dependent secretory process in neuroendocrine cells. In lactotroph cells Rab3b seems to play a stimulatory role, whereas Rab3a acts as a negative regulator of catecholamine release in chromaffin cells.