Genetic analysis of synaptotagmin 2 in spontaneous and Ca2+-triggered neurotransmitter release.
Synaptotagmin 2 resembles synaptotagmin 1, the Ca2+ sensor for fast neurotransmitter release in forebrain synapses, but little is known about synaptotagmin 2 function. Here, we describe a severely ataxic mouse strain that harbors a single, destabilizing amino-acid substitution (I377N) in synaptotagmin 2. In Calyx of Held synapses, this mutation causes a delay and a decrease in Ca2+-induced but not in hypertonic sucrose-induced release, suggesting that synaptotagmin 2 mediates Ca2+ triggering of evoked release in brainstem synapses. Unexpectedly, we additionally observed in synaptotagmin 2 mutant synapses a dramatic increase in spontaneous release. Synaptotagmin 1-deficient excitatory and inhibitory cortical synapses also displayed a large increase in spontaneous release, demonstrating that this effect was shared among synaptotagmins 1 and 2. Our data suggest that synaptotagmin 1 and 2 perform equivalent functions in the Ca2+ triggering of action potential-induced release and in the restriction of spontaneous release, consistent with a general role of synaptotagmins in controlling 'release slots' for synaptic vesicles at the active zone.
Pang
Zhiping P
ZP
Department of Molecular Genetics, Center for Basic Neuroscience, Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, TX 75390-9111, USA.
Sun
Jianyuan
J
Rizo
Josep
J
Maximov
Anton
A
Südhof
Thomas C
TC
D000200:Action Potentials / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D001259:Ataxia / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000033:anatomy & histology; D002118:Calcium / Q000378:metabolism*; D066298:In Vitro Techniques; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D017354:Point Mutation; D011489:Protein Denaturation; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D050863:Synaptotagmin I / Q000235:genetics / Q000378:metabolism; D050861:Synaptotagmin II / Q000235:genetics / Q000378:metabolism
D018377:Neurotransmitter Agents; D050863:Synaptotagmin I; D050861:Synaptotagmin II; C494311:Syt1 protein, mouse; C494263:Syt2 protein, mouse; D002118:Calcium