Soluble α-synuclein facilitates priming and fusion by releasing Ca2+ from the thapsigargin-sensitive Ca2+ pool in PC12 cells

α-Synuclein is associated with Parkinson's disease. α-Synuclein is mainly localized in presynaptic terminals and regulates exocytosis, but its physiological roles remain controversial. We studied effects of soluble and aggregated α-synuclein on exocytosis and explored the molecular mechanism by which α-synuclein interacts with regulatory proteins, including Rab3A, Munc13-1 and Munc18-1, in order to regulate exocytosis. Using fluorescence recovery after photobleaching, overexpressed α-synuclein in PC12 cells was found to be in a monomeric form, which promotes exocytosis. In contrast, aggregated α-synuclein induced by lactacystin inhibits exocytosis. Our results show that α-synuclein is involved in vesicle priming and fusion. α-Synuclein and PMA, which is known to enhance vesicle priming mediated by Rab3A, Munc13-1 and Munc18-1, act on the same population of vesicles, but regulate priming independently. Furthermore, the results show a novel effects of α-synuclein on mobilizing Ca2+ release from thapsigargin-sensitive calcium pools to enhance the ATP-induced [Ca2+]i increase, which enhances vesicle fusion. Our results provide a detailed understanding of the action of α-synuclein during the final steps of exocytosis.