Synaptotagmin VII as a plasma membrane Ca2+ sensor in exocytosis

Synaptotagmins I and II are Ca2+ binding proteins of synaptic vesicles esse ntial for fast Ca2+-triggered neurotransmitter release. However, central sy napses 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 vesic ular synaptotagmins. We show that alternatively spliced forms of synaptotag min VII are expressed in a developmentally regulated pattern in brain and a re concentrated in presynaptic active zones of central synapses. In neuroen docrine PC12 cells, the C(2)A and C2B domains of synaptotagmin VII are pote nt inhibitors of Ca2+-dependent exocytosis, but only when they bind Ca2+, O ur data suggest that in synaptic vesicle exocytosis, distinct synaptotagmin s function as independent Ca2+ sensors on the two fusion partners, the plas ma membrane (synaptotagmin VII) versus synaptic vesicles (synaptotagmins I and II).