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Angiotensin II (AngII) receptors couple to a multitude of different types of G-proteins resulting in activation of numerous signaling pathways. In this study we examined the consequences of this promiscuous G-protein coupling on secretion. Chromaffin cells were voltage-clamped at −80 mV in perforated-patch configuration, and Ca2+-dependent exocytosis was evoked with brief voltage steps to +20 mV. Vesicle fusion was monitored by changes in membrane capacitance (ΔCm), and released catecholamine was detected with single-cell amperometry. Ca2+ signaling was studied by recording voltage-dependent Ca2+ currents (ICa) and by measuring intracellular Ca2+([Ca2+]i) with fura-2 AM. AngII inhibited ICa (IC50 = 0.3 nm) in a voltage-dependent, pertussis toxin (PTX)-sensitive manner consistent with Gi/o-protein coupling to Ca2+ channels. ΔCm was modulated bi-directionally; subnanomolar AngII inhibited depolarization-evoked exocytosis, whereas higher concentrations, in spite of ICainhibition, potentiated ΔCm fivefold (EC50 = 3.4 nm). Potentiation of exocytosis by AngII involved activation of phospholipase C (PLC) and Ca2+ mobilization from internal stores. PTX treatment did not affect AngII-dependent Ca2+mobilization or facilitation of exocytosis. However, protein kinase C (PKC) inhibitors decreased the facilitatory effects but not the inhibitory effects of AngII on stimulus-secretion coupling. The AngII type 1 receptor (AT1R) antagonist losartan blocked both inhibition and facilitation of secretion by AngII. The results of this study show that activation of multiple types of G-proteins and transduction pathways by a single neuromodulator acting through one receptor type can produce concentration-dependent, bi-directional regulation of exocytosis.

Bidirectional Modulation of Exocytosis by Angiotensin II Involves Multiple G-Protein-Regulated Transduction Pathways in Chromaffin Cells