Synaptotagmin VII as a plasma membrane Ca2+ sensor in exocytosis

Synaptotagmins I and II are Ca2+ binding proteins of synaptic vesicles essential for fast Ca2+-triggered neurotransmitter release. However, central synapses and neuroendocrine cells lacking these synaptotagmins still exhibit Ca2+-evoked exocytosis. We now propose that synaptotagmin VII functions as a plasma membrane Ca2+ sensor in synaptic exocytosis complementary to vesicular synaptotagmins. We show that alternatively spliced forms of synaptotagmin VII are expressed in a developmentally regulated pattern in brain and are concentrated in presynaptic active zones of central synapses. In neuroendocrine PC12 cells, the C(2)A and C2B domains of synaptotagmin VII are potent inhibitors of Ca2+-dependent exocytosis, but only when they bind Ca2+, Our data suggest that in synaptic vesicle exocytosis, distinct synaptotagmins function as independent Ca2+ sensors on the two fusion partners, the plasma membrane (synaptotagmin VII) versus synaptic vesicles (synaptotagmins I and II).