SV2 acts via presynaptic calcium to regulate neurotransmitter release.
Synaptic vesicle 2 (SV2) proteins, critical for proper nervous system function, are implicated in human epilepsy, yet little is known about their function. We demonstrate, using direct approaches, that loss of the major SV2 isoform in a central nervous system nerve terminal is associated with an elevation in both resting and evoked presynaptic Ca(2+) signals. This increase is essential for the expression of the SV2B(-/-) secretory phenotype, characterized by changes in synaptic vesicle dynamics, synaptic plasticity, and synaptic strength. Short-term reproduction of the Ca(2+) phenotype in wild-type nerve terminals reproduces almost all aspects of the SV2B(-/-) secretory phenotype, while rescue of the Ca(2+) phenotype in SV2B(-/-) neurons relieves every facet of the SV2B(-/-) secretory phenotype. Thus, SV2 controls key aspects of synaptic functionality via its ability to regulate presynaptic Ca(2+), suggesting a potential new target for therapeutic intervention in the treatment of epilepsy.
Wan
Qun-Fang
QF
The Department of Neurobiology and Anatomy, University of Texas Medical School at Houston, Houston, TX 77030, USA.
Zhou
Zhen-Yu
ZY
Thakur
Pratima
P
Vila
Alejandro
A
Sherry
David M
DM
Janz
Roger
R
Heidelberger
Ruth
R
D000429:Alcohol Oxidoreductases; D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000235:genetics / Q000502:physiology; D002614:Chelating Agents / Q000494:pharmacology; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D004533:Egtazic Acid / Q000494:pharmacology; D004558:Electric Stimulation / Q000379:methods; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D018408:Patch-Clamp Techniques / Q000379:methods; D010750:Phosphoproteins / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000648:ultrastructure; D051571:Protein Kinase C-alpha / Q000378:metabolism; D012160:Retina / Q000166:cytology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism* / Q000648:ultrastructure
D002614:Chelating Agents; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D010750:Phosphoproteins; C489615:Sv2b protein, mouse; D004533:Egtazic Acid; D000429:Alcohol Oxidoreductases; C111341:Ctbp2 protein, mouse; D051571:Protein Kinase C-alpha; D002118:Calcium