Munc13-1 is required for the sustained release of insulin from pancreatic beta cells.
Munc13-1 is a presynaptic protein that is essential for synaptic vesicle priming. Deletion of Munc13-1/unc13 causes total arrest of synaptic transmission due to a complete loss of fusion-competent synaptic vesicles. The requirement of Munc13-1 for large dense-core vesicles (LDCVs), however, has not been established. In the present study, we use Munc13-1 knockout (KO) and diacylglycerol (DAG) binding-deficient Munc13-1(H567K) mutant knockin (KI) mice to determine the role of Munc13-1 in the secretion of insulin-containing LDCVs from primary cultured pancreatic beta cells. We show that Munc13-1 is required for the sustained insulin release upon prolonged stimulation. The sustained release involves signaling of DAG second messenger, since it is also reduced in KI mice. Insulin secretion in response to glucose stimulation is characterized by a biphasic time course. Our data show that Munc13-1 plays an essential role in the development of the second phase of insulin secretion by priming insulin-containing LDCVs.
Kang
Lijun
L
Joint Laboratory of Huazhong University of Science and Technology and Institute of Biophysics, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
He
Zixuan
Z
Xu
Pingyong
P
Fan
Junmei
J
Betz
Andrea
A
Brose
Nils
N
Xu
Tao
T
D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004075:Diglycerides / Q000502:physiology; D005089:Exocytosis / Q000502:physiology; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D022142:Secretory Vesicles / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors
D004075:Diglycerides; D007328:Insulin; D009419:Nerve Tissue Proteins; C503321:Unc13a protein, mouse; D005947:Glucose; D002118:Calcium