The Role of Calmodulin vs. Synaptotagmin in Exocytosis

Exocytosis is a Ca(2+)-regulated process that requires the participation of Ca(2+) sensors. In the 1980s, two classes of Ca(2+)-binding proteins were proposed as putative Ca(2+) sensors: EF-hand protein calmodulin, and the C2 domain protein synaptotagmin. In the next few decades, numerous studies determined that in the final stage of membrane fusion triggered by a micromolar boost in the level of Ca(2+), the low affinity Ca(2+)-binding protein synaptotagmin, especially synaptotagmin 1 and 2, acts as the primary Ca(2+) sensor, whereas calmodulin is unlikely to be functional due to its high Ca(2+) affinity. However, in the meantime emerging evidence has revealed that calmodulin is involved in the earlier exocytotic steps prior to fusion, such as vesicle trafficking, docking and priming by acting as a high affinity Ca(2+) sensor activated at submicromolar level of Ca(2+). Calmodulin directly interacts with multiple regulatory proteins involved in the regulation of exocytosis, including VAMP, myosin V, Munc13, synapsin, GAP43 and Rab3, and switches on key kinases, such as type II Ca(2+)/calmodulin-dependent protein kinase, to phosphorylate a series of exocytosis regulators, including syntaxin, synapsin, RIM and Ca(2+) channels. Moreover, calmodulin interacts with synaptotagmin through either direct binding or indirect phosphorylation. In summary, calmodulin and synaptotagmin are Ca(2+) sensors that play complementary roles throughout the process of exocytosis. In this review, we discuss the complementary roles that calmodulin and synaptotagmin play as Ca(2+) sensors during exocytosis.