Nature Neuroscience5, 649 - 656 (2002)
Published online: 10 June 2002; | doi:10.1038/nn869
Synaptotagmin function in dense core vesicle exocytosis studied in cracked PC12 cells
Ok-Ho Shin1, Josep Rizo2
& Thomas C. Südhof1
1
Center for Basic Neuroscience, Department of Molecular Genetics and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, Texas 75390, USA.
2
Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, Texas 75390, USA.
Ca2+-triggered dense-core vesicle exocytosis in PC12 cells does not require vesicular synaptotagmins 1 and 2, but may use plasma membrane synaptotagmins 3 and 7 as Ca2+ sensors. In support of this hypothesis, C2 domains from the plasma membrane but not vesicular synaptotagmins inhibit PC12 cell exocytosis. Ca2+ induces binding of both plasma membrane and vesicular synaptotagmins to phospholipids and SNAREs (soluble N-ethylmaleimide-sensitive attachment protein receptors), although with distinct apparent Ca2+ affinities. Here we used gain-of-function C2-domain mutants of synaptotagmin 1 and loss-of-function C2-domain mutants of synaptotagmin 7 to examine how synaptotagmins function in dense-core vesicle exocytosis. Our data indicate that phospholipid- but not SNARE-binding by plasma membrane synaptotagmins is the primary determinant of Ca2+-triggered dense-core vesicle exocytosis. These results support a general lipid-based mechanism of action of synaptotagmins in exocytosis, with the specificity of various synaptotagmins for different types of fusion governed by their differential localizations and Ca2+ affinities.
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