Synaptotagmin-12, a synaptic vesicle phosphoprotein that modulates spontaneous neurotransmitter release.
Central synapses exhibit spontaneous neurotransmitter release that is selectively regulated by cAMP-dependent protein kinase A (PKA). We now show that synaptic vesicles contain synaptotagmin-12, a synaptotagmin isoform that differs from classical synaptotagmins in that it does not bind Ca(2+). In synaptic vesicles, synaptotagmin-12 forms a complex with synaptotagmin-1 that prevents synaptotagmin-1 from interacting with SNARE complexes. We demonstrate that synaptotagmin-12 is phosphorylated by cAMP-dependent PKA on serine(97), and show that expression of synaptotagmin-12 in neurons increases spontaneous neurotransmitter release by approximately threefold, but has no effect on evoked release. Replacing serine(97) by alanine abolishes synaptotagmin-12 phosphorylation and blocks its effect on spontaneous release. Our data suggest that spontaneous synaptic-vesicle exocytosis is selectively modulated by a Ca(2+)-independent synaptotagmin isoform, synaptotagmin-12, which is controlled by cAMP-dependent phosphorylation.
Maximov
Anton
A
Center for Basic Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Shin
Ok-Ho
OH
Liu
Xinran
X
Südhof
Thomas C
TC
D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D006031:Glycosylation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000648:ultrastructure; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D051379:Mice; D008969:Molecular Sequence Data; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism*; D050863:Synaptotagmin I / Q000378:metabolism; D050857:Synaptotagmins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D018377:Neurotransmitter Agents; D010743:Phospholipids; D010750:Phosphoproteins; D050863:Synaptotagmin I; D050857:Synaptotagmins; D010768:Phosphoserine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium