Stimulation of exocytosis without a calcium signal

More than 30 years ago, Douglas (Douglas & Rubin, 1961; Douglas, 1968) prop osed that intracellular Ca2+ controls stimulus-secretion coupling in endocr ine cells, and Katz & Miledi (1967; Katz, 1969) proposed that intracellular Ca2+ ions control the rapid release of neurotransmitters from synapses. Th ese related hypotheses have been amply confirmed in subsequent years and fo r students of excitable cells, they dominate our teaching and research. Cal cium controls regulated exocytosis. On the other hand, many studies of epit helial and blood cell biology emphasize Ca2+-independent regulation of secr etion of mucin, exocytotic delivery of transporters and degranulation. The evidence seems good. Are these contrasting conclusions somehow mistaken, or are the dominant factors controlling exocytosis actually different in diff erent cell types? In this essay, we try to reconcile these ideas and consid er classes of questions to ask and hypotheses to test in seeking a more int egrated understanding of excitation-secretion coupling. Our review is conce ptual and narrowly selective of a few examples rather than referring to a b roader range of useful studies in the extensive literature. The examples ar e taken from mammals and are documented principally by citing other reviews and two of our own studies. The evidence shows that protein phosphorylatio n by kinases potentiates Ca2+-dependent exocytosis and often suffices to in duce exocytosis by itself. Apparently, protein phosphorylation is the physi ological trigger in a significant number of examples of regulated exocytosi s. We conclude that although sharing many common properties, secretory proc esses in different cells are specialized and distinct from each other.