Autonomous function of synaptotagmin 1 in triggering synchronous release independent of asynchronous release.
Ca(2+) triggers neurotransmitter release in at least two principal modes, synchronous and asynchronous release. Synaptotagmin 1 functions as a Ca(2+) sensor for synchronous release, but its role in asynchronous release remains unclear. We now show that in cultured cortical neurons stimulated at low frequency (<or.1 Hz), deletion of synaptotagmin 1 blocks synchronous GABA and glutamate release without significantly increasing asynchronous release. At higher stimulation frequencies (>or Hz), deletion of synaptotagmin 1 also alters only synchronous, not asynchronous, release during the stimulus train, but dramatically enhances "delayed asynchronous release" following the stimulus train. Thus synaptotagmin 1 functions as an autonomous Ca(2+) sensor independent of asynchronous release during isolated action potentials and action potential trains, but restricts asynchronous release induced by residual Ca(2+) after action potential trains. We propose that synaptotagmin 1 occupies release "slots" at the active zone, possibly in a Ca(2+)-independent complex with SNARE proteins that are freed when action potential-induced Ca(2+) influx activates synaptotagmin 1.
Maximov
Anton
A
Center for Basic Neuroscience, Department of Molecular Genetics, and Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Südhof
Thomas C
TC
D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism; D009433:Neural Inhibition / Q000502:physiology; D009474:Neurons / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology; D050863:Synaptotagmin I / Q000172:deficiency / Q000502:physiology*; D013997:Time Factors
D007476:Ionophores; D018377:Neurotransmitter Agents; D050863:Synaptotagmin I; D004533:Egtazic Acid; D015759:Ionomycin; C046770:EGTA acetoxymethyl ester; D002118:Calcium