Novel aspects of the molecular mechanisms controlling insulin secretion

Novel aspects of the molecular mechanisms controlling insulin secretion Pancreatic β‐cells secrete insulin by Ca2+‐dependent exocytosis of secretory granules. β‐cell exocytosis involves SNARE (soluble NSF‐attachment protein receptor) proteins similar to those controlling neurotransmitter release and depends on the close association of L‐type Ca2+ channels and granules. In most cases, the secretory granules fuse individually but there is ultrastructural and biophysical evidence of multivesicular exocytosis. Estimates of the secretory rate in β‐cells in intact islets indicate a release rate of ∼15 granules per β‐cell per second, 100‐fold higher than that observed in biochemical assays. Single‐vesicle capacitance measurements reveal that the diameter of the fusion pore connecting the granule lumen with the exterior is ∼1.4 nm. This is considerably smaller than the size of insulin and membrane fusion is therefore not obligatorily associated with release of the cargo, a feature that may contribute to the different rates of secretion detected by the biochemical and biophysical measurements. However, small molecules like ATP and GABA, which are stored together with insulin in the granules, are small enough to be released via the narrow fusion pore, which accordingly functions as a molecular sieve. We finally consider the possibility that defective fusion pore expansion accounts for the decrease in insulin secretion observed in pathophysiological states including long‐term exposure to lipids. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Physiology Wiley

Novel aspects of the molecular mechanisms controlling insulin secretion

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Publisher
Wiley
Copyright
© 2008 The Authors. Journal compilation © 2008 The Physiological Society
ISSN
0022-3751
eISSN
1469-7793
D.O.I.
10.1113/jphysiol.2008.155317
Publisher site
See Article on Publisher Site

Abstract

Pancreatic β‐cells secrete insulin by Ca2+‐dependent exocytosis of secretory granules. β‐cell exocytosis involves SNARE (soluble NSF‐attachment protein receptor) proteins similar to those controlling neurotransmitter release and depends on the close association of L‐type Ca2+ channels and granules. In most cases, the secretory granules fuse individually but there is ultrastructural and biophysical evidence of multivesicular exocytosis. Estimates of the secretory rate in β‐cells in intact islets indicate a release rate of ∼15 granules per β‐cell per second, 100‐fold higher than that observed in biochemical assays. Single‐vesicle capacitance measurements reveal that the diameter of the fusion pore connecting the granule lumen with the exterior is ∼1.4 nm. This is considerably smaller than the size of insulin and membrane fusion is therefore not obligatorily associated with release of the cargo, a feature that may contribute to the different rates of secretion detected by the biochemical and biophysical measurements. However, small molecules like ATP and GABA, which are stored together with insulin in the granules, are small enough to be released via the narrow fusion pore, which accordingly functions as a molecular sieve. We finally consider the possibility that defective fusion pore expansion accounts for the decrease in insulin secretion observed in pathophysiological states including long‐term exposure to lipids.

Journal

The Journal of PhysiologyWiley

Published: Jul 15, 2008

References

  • Exocytosis elicited by action potentials and voltage‐clamp calcium currents in individual mouse pancreatic B‐cells
    Ammala, Ammala; Eliasson, Eliasson; Bokvist, Bokvist; Larsson, Larsson; Ashcroft, Ashcroft; Rorsman, Rorsman
  • Long‐term exposure of mouse pancreatic islets to oleate or palmitate results in reduced glucose‐induced somatostatin and oversecretion of glucagon
    Collins, Collins; Salehi, Salehi; Eliasson, Eliasson; Olofsson, Olofsson; Rorsman, Rorsman
  • SUR1 regulates PKA‐independent cAMP‐induced granule priming in mouse pancreatic B‐cells
    Eliasson, Eliasson; Ma, Ma; Renström, Renström; Barg, Barg; Berggren, Berggren; Galvanovskis, Galvanovskis; Gromada, Gromada; Jing, Jing; Lundquist, Lundquist; Salehi, Salehi; Sewing, Sewing; Rorsman, Rorsman
  • Neural cell adhesion molecule (N‐CAM) is required for cell type segregation and normal ultrastructure in pancreatic islets
    Esni, Esni; Taljedal, Taljedal; Perl, Perl; Cremer, Cremer; Christofori, Christofori; Semb, Semb
  • CaM kinase II‐dependent mobilization of secretory granules underlies acetylcholine‐induced stimulation of exocytosis in mouse pancreatic B‐cells
    Gromada, Gromada; Høy, Høy; Renström, Renström; Bokvist, Bokvist; Eliasson, Eliasson; Göpel, Göpel; Rorsman, Rorsman
  • Temperature‐sensitive random insulin granule diffusion is a prerequisite for recruiting granules for release
    Ivarsson, Ivarsson; Obermüller, Obermüller; Rutter, Rutter; Galvanovskis, Galvanovskis; Renström, Renström
  • Imaging analysis reveals mechanistic differences between first‐ and second‐phase insulin exocytosis
    Ohara‐Imaizumi, Ohara‐Imaizumi; Fujiwara, Fujiwara; Nakamichi, Nakamichi; Okamura, Okamura; Akimoto, Akimoto; Kawai, Kawai; Matsushima, Matsushima; Kawakami, Kawakami; Watanabe, Watanabe; Akagawa, Akagawa; Nagamatsu, Nagamatsu
  • Fast insulin secretion reflects exocytosis of docked granules in mouse pancreatic B‐cells
    Olofsson, Olofsson; Göpel, Göpel; Barg, Barg; Galvanovskis, Galvanovskis; Ma, Ma; Salehi, Salehi; Rorsman, Rorsman; Eliasson, Eliasson
  • PKA‐dependent and PKA‐independent pathways for cAMP‐regulated exocytosis
    Seino, Seino; Shibasaki, Shibasaki
  • nSec1 binds a closed conformation of syntaxin1A
    Yang, Yang; Steegmaier, Steegmaier; Gonzalez, Gonzalez; Scheller, Scheller

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