Exocytosis of Insulin

Stable Identifier
R-HSA-265166
Type
Reaction [omitted]
Species
Homo sapiens
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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 particular 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. Unc18-1 binds Syntaxin1A and thereby prevents association with Synaptobrevin2 until dissociation of Unc18-1. 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, 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.

The major effect of adrenaline and noradrenaline on insulin secretion is the inhibition of exocytosis of pre-existing insulin secretory granules. The inhibition occurs at a "distal site", that is, the effect is most pronounced on granules already near the cytosolic face of the plasma membrane. The effect is caused by the Gi/o alpha:GTP complex but the exact mechanism by which Gi/o alpha:GTP inhibits exocytosis is unknown. On release, the higher pH in the extracellular region favours dissociation of Zn2+ from insulin. The insulin hexamer becomes unstable at this higher pH and it dissociates into the active insulin monomer.

Literature References
PubMed ID Title Journal Year
12403834 Synaptosome-associated protein of 25 kilodaltons modulates Kv2.1 voltage-dependent K(+) channels in neuroendocrine islet beta-cells through an interaction with the channel N terminus

MacDonald, PE, Wang, G, Tsuk, S, Dodo, C, Kang, Y, Tang, L, Wheeler, MB, Cattral, MS, Lakey, JR, Salapatek, AM, Lotan, I, Gaisano, HY

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

Rutter, GA, Hill, EV

Physiology (Bethesda) 2006
11815463 Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion

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

Diabetes 2002
9914469 Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrine secretion

Lang, J

Eur J Biochem 1999
17900700 G-protein-coupled receptors and islet function-implications for treatment of type 2 diabetes

Winzell, MS, Ahren, B

Pharmacol Ther 2007
16443778 Impaired gene and protein expression of exocytotic soluble N-ethylmaleimide attachment protein receptor complex proteins in pancreatic islets of type 2 diabetic patients

Ostenson, CG, Gaisano, H, Sheu, L, Tibell, A, Bartfai, T

Diabetes 2006
12684222 Protein acylation in the inhibition of insulin secretion by norepinephrine, somatostatin, galanin, and PGE2

Cheng, H, Straub, SG, Sharp, GW

Am J Physiol Endocrinol Metab 2003
15572341 Insulin secretion: a high-affinity Ca2+ sensor after all?

Barg, S, Rorsman, P

J Gen Physiol 2004
11815450 Molecular determinants of regulated exocytosis

Gerber, SH, S├╝dhof, TC

Diabetes 2002
8997178 Mechanisms of inhibition of insulin release

Sharp, GW

Am J Physiol 1996
18162464 Both G i and G o heterotrimeric G proteins are required to exert the full effect of norepinephrine on the beta-cell K ATP channel

Zhao, Y, Fang, Q, Straub, SG, Sharp, GW

J Biol Chem 2008
12887316 Insulin secretion by 'kiss-and-run' exocytosis in clonal pancreatic islet beta-cells

Tsuboi, T, Rutter, GA

Biochem Soc Trans 2003
14514350 Inhibition of insulin secretion via distinct signaling pathways in alpha2-adrenoceptor knockout mice

Peterhoff, M, Sieg, A, Brede, M, Chao, CM, Hein, L, Ullrich, S

Eur J Endocrinol 2003
7641683 Direct control of exocytosis by receptor-mediated activation of the heterotrimeric GTPases Gi and G(o) or by the expression of their active G alpha subunits

Lang, J, Nishimoto, I, Okamoto, T, Regazzi, R, Kiraly, C, Weller, U, Wollheim, CB

EMBO J 1995
11873862 Norepinephrine inhibits glucose-stimulated, Ca2+-independent insulin release independently from its action on adenylyl cyclase

Yajima, H, Komatsu, M, Sato, Y, Yamada, S, Yamauchi, K, Sharp, GW, Aizawa, T, Hashizume, K

Endocr J 2001
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Title
SNARE binding activity of Core SNARE Complex [plasma membrane]
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