TY - JOUR
T1 - Munc13-1 and Munc18-1 together prevent NSF-dependent de-priming of synaptic vesicles
AU - He, Enqi
AU - Wierda, Keimpe
AU - Van Westen, Rhode
AU - Broeke, Jurjen H.
AU - Toonen, Ruud F.
AU - Cornelisse, L. Niels
AU - Verhage, Matthijs
PY - 2017/6/21
Y1 - 2017/6/21
N2 - Synaptic transmission requires a stable pool of release-ready (primed) vesicles. Here we show that two molecules involved in SNARE-complex assembly, Munc13-1 and Munc18-1, together stabilize release-ready vesicles by preventing de-priming. Replacing neuronal Munc18-1 by a non-neuronal isoform Munc18-2 (Munc18-1/2SWAP) supports activity-dependent priming, but primed vesicles fall back into a non-releasable state (de-prime) within seconds. Munc13-1 deficiency produces a similar defect. Inhibitors of N-ethylmaleimide sensitive factor (NSF), N-ethylmaleimide (NEM) or interfering peptides, prevent de-priming in munc18-1/2SWAP or munc13-1 null synapses, but not in CAPS-1/2 null, another priming-deficient mutant. NEM rescues synaptic transmission in munc13-1 null and munc18-1/2SWAP synapses, in acute munc13-1 null slices and even partially in munc13-1/2 double null synapses. Together these data indicate that Munc13-1 and Munc18-1, but not CAPS-1/2, stabilize primed synaptic vesicles by preventing NSF-dependent de-priming.
AB - Synaptic transmission requires a stable pool of release-ready (primed) vesicles. Here we show that two molecules involved in SNARE-complex assembly, Munc13-1 and Munc18-1, together stabilize release-ready vesicles by preventing de-priming. Replacing neuronal Munc18-1 by a non-neuronal isoform Munc18-2 (Munc18-1/2SWAP) supports activity-dependent priming, but primed vesicles fall back into a non-releasable state (de-prime) within seconds. Munc13-1 deficiency produces a similar defect. Inhibitors of N-ethylmaleimide sensitive factor (NSF), N-ethylmaleimide (NEM) or interfering peptides, prevent de-priming in munc18-1/2SWAP or munc13-1 null synapses, but not in CAPS-1/2 null, another priming-deficient mutant. NEM rescues synaptic transmission in munc13-1 null and munc18-1/2SWAP synapses, in acute munc13-1 null slices and even partially in munc13-1/2 double null synapses. Together these data indicate that Munc13-1 and Munc18-1, but not CAPS-1/2, stabilize primed synaptic vesicles by preventing NSF-dependent de-priming.
KW - Journal Article
UR - http://www.scopus.com/inward/record.url?scp=85021094903&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85021094903&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/ncomms15915
DO - https://doi.org/10.1038/ncomms15915
M3 - Article
C2 - 28635948
SN - 2041-1723
VL - 8
SP - 15915
JO - Nature communications
JF - Nature communications
M1 - 15915
ER -
