Synaptotagmin VII as a plasma membrane Ca(2+) sensor in exocytosis.
Synaptotagmins I and II are Ca(2+) binding proteins of synaptic vesicles essential for fast Ca(2+)-triggered neurotransmitter release. However, central synapses and neuroendocrine cells lacking these synaptotagmins still exhibit Ca(2+)-evoked exocytosis. We now propose that synaptotagmin VII functions as a plasma membrane Ca(2+) 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 C(2)B domains of synaptotagmin VII are potent inhibitors of Ca(2+)-dependent exocytosis, but only when they bind Ca(2+). Our data suggest that in synaptic vesicle exocytosis, distinct synaptotagmins function as independent Ca(2+) sensors on the two fusion partners, the plasma membrane (synaptotagmin VII) versus synaptic vesicles (synaptotagmins I and II).
Sugita
S
S
Center for Basic Neuroscience, Department of Molecular Genetics and, Howard Hughes Medical Institute, The University of Texas Southwestern, Medical Center, 6000 Harry Hines Boulevard NA4.118, Dallas TX 75390, USA.
Han
W
W
Butz
S
S
Liu
X
X
Fernández-Chacón
R
R
Lao
Y
Y
Südhof
T C
TC
D000375:Aging; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000254:growth & development / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002462:Cell Membrane / Q000502:physiology*; D003001:Cloning, Molecular; D004622:Embryo, Mammalian; D005089:Exocytosis / Q000502:physiology*; D005091:Exons; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins / Q000032:analysis / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009928:Organ Specificity; D016716:PC12 Cells; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013569:Synapses / Q000502:physiology*; D050857:Synaptotagmins; D014162:Transfection
D002135:Calcium-Binding Proteins; D008164:Luminescent Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; C494303:Syt7 protein, mouse; C494304:Syt7 protein, rat; D050857:Synaptotagmins; D049452:Green Fluorescent Proteins; D002118:Calcium