Exocytosis of Insulin

Stable Identifier
R-MMU-216883
Type
Reaction [omitted]
Species
Mus musculus
Compartment
plasma membrane
ReviewStatus
5/5
General
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PNG
Low
Medium
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Exocytosis of Insulin
Exocytosis of insulin-zinc granules occurs by the calcium-dependent fusion of the membrane of the secretory granule with the plasma membrane. In general, exocytosis proceeds by formation of a "SNARE pair", a complex between a SNARE-type protein on the granule and a SNARE-type protein on the plasma membrane. (The interaction is between coiled coil domains on each SNARE-type protein.)
In the particluar case of insulin granules in beta cells, the SNARE protein on the granule is Synaptobrevin2/VAMP2 and the SNARE protein on the plasma membrane is Syntaxin1A in a complex with SNAP-25. Munc18-1 binds Syntaxin1A and thereby prevents association with Synaptobrevin2 until dissociation of Munc18-1. Syntaxin 4 is also involved and binds filamentous actin but its exact role is unknown.
Insulin exocytosis occurs in two phases: 1) a rapid release of about 100 of the 1000 docked granules within the first 5 minutes of glucose stimulation and 2) a subsequent slow release over 30 minutes or more due to migration of internal granules to the plasma membrane. Data from knockout mice show that Syntaxin 1A is involved in rapid release but not slow release, whereas Syntaxin 4 is involved in both types of release.
Calcium dependence of membrane fusion is conferred by Synaptotagmin V/IX, which binds calcium ions and associates with the Syntaxin1A-Synaptobrevin2 pair. The exact mechanism of Synaptotagmin's action is unknown. The migration of internal granules to the plasma membrane during slow release is also calcium dependent.
Microscopically, exocytosis is seen to occur as a "kiss and run" process in which the membrane of the secretory granule fuses transiently with the plasma membrane to form a small pore of about 4 nm between the interior of the granule and the exterior of the cell. Only a portion of the insulin in a granule is secreted after which the pore closes and the vesicle is recaptured back into the cell. Dynamin-1 and NSF may play a role in recapture but the mechanism is not fully known.
Literature References
PubMed ID Title Journal Year
15537656 A direct interaction between Cdc42 and vesicle-associated membrane protein 2 regulates SNARE-dependent insulin exocytosis

Nevins, AK, Thurmond, DC

J Biol Chem 2005
14676208 Site of docking and fusion of insulin secretory granules in live MIN6 beta cells analyzed by TAT-conjugated anti-syntaxin 1 antibody and total internal reflection fluorescence microscopy

Nakamichi, Y, Kumakura, K, Ohara-Imaizumi, M, Nagamatsu, S, Nishiwaki, C, Kikuta, T

J Biol Chem 2004
16720719 Antibody inhibition of synaptosomal protein of 25 kDa (SNAP-25) and syntaxin 1 reduces rapid exocytosis in insulin-secreting cells

Hockerman, GH, Ma, X, Eliasson, L, Vikman, J, Rorsman, P

J Mol Endocrinol 2006
11309201 Expression and localisation of synaptotagmin isoforms in endocrine beta-cells: their function in insulin exocytosis

Fukuda, M, Mikoshiba, K, Kiraly, CE, Lang, J, Gut, A, Wollheim, CB

J Cell Sci 2001
12887316 Insulin secretion by 'kiss-and-run' exocytosis in clonal pancreatic islet beta-cells

Rutter, GA, Tsuboi, T

Biochem Soc Trans 2003
19188424 Munc18c depletion selectively impairs the sustained phase of insulin release

Oh, E, Thurmond, DC

Diabetes 2009
11815450 Molecular determinants of regulated exocytosis

Gerber, SH, Südhof, TC

Diabetes 2002
17502420 Imaging analysis reveals mechanistic differences between first- and second-phase insulin exocytosis

Kawai, J, Akimoto, Y, Akagawa, K, Nakamichi, Y, Okamura, T, Matsushima, S, Ohara-Imaizumi, M, Nagamatsu, S, Watanabe, T, Fujiwara, T, Kawakami, H

J Cell Biol 2007
10480595 Identification of the docked granule pool responsible for the first phase of glucose-stimulated insulin secretion

Straub, SG, Sharp, GW, Noda, M, Daniel, S

Diabetes 1999
7556990 Role of syntaxin in mouse pancreatic beta cells

Moya, F, Gutierrez, LM, Reig, JA, Soria, B, Martin, F

Diabetologia 1995
15572341 Insulin secretion: a high-affinity Ca2+ sensor after all?

Rorsman, P, Barg, S

J Gen Physiol 2004
16099818 Syntaxin 4 facilitates biphasic glucose-stimulated insulin secretion from pancreatic beta-cells

Spurlin, BA, Thurmond, DC

Mol Endocrinol 2006
9914469 Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrine secretion

Lang, J

Eur J Biochem 1999
11815463 Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion

Straub, SG, Yajima, H, Gunawardana, S, Sharp, GW, Daniel, S, Bratanova-Tochkova, TK, Mulvaney-Musa, J, Cheng, H, Schermerhorn, T, Liu, YJ

Diabetes 2002
16714477 Insulin vesicle release: walk, kiss, pause ... then run

Rutter, GA, Hill, EV

Physiology (Bethesda) 2006
Participants
Input
Output
Catalyst Activity

calcium ion binding activity of Synaptotagmin V/IX [plasma membrane]

Physical Entity
Synaptotagmin V/IX [plasma membrane] (Mus musculus)
Activity
calcium ion binding (GO:0005509)
Orthologous Events
Exocytosis of Insulin (Homo sapiens)
Authored
May, B  (2008-11-20)
Gopinathrao, G  (2008-11-20)
Reviewed
May, B  (2009-10-31)
Created
May, B  (2008-03-24)
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