Caffeine-induced transmitter release is mediated via ryanodine-sensitive channel.

An isolated clone PC12-37 of rat pheochromocytoma PC12 cells, which lacks ryanodine-sensitive Ca2+ channel, responds to depolarization and to agonist activation and triggers [3H]dopamine ([3H]DA) release. A caffeine-stimulated transmitter release, while present in the parental PC12 cell line, is completely abolished in PC12-37 cells. In contrast, caffeine-induced Ca2+ influx in PC12-37 cells is similar to that observed in PC12 cells, indicating that caffeine-induced CA2+ influx is neither mediated by caffeine-induced Ca2+ release nor contributes to the caffeine-induced secretion. These results show (a) a tight coupling between caffeine activation of a ryanodine-sensitive Ca2+ store and transmitter release, (b) no significant involvement of the ryanodine-sensitive Ca2+ channel in depolarization- and agonist-mediated transmitter release, and (c) exclude a major role for caffeine-mediated Ca2+ entry in the caffeine-activated secretion.