Reactome | Adrenaline,noradrenaline inhibits insulin secretion

Adrenaline,noradrenaline inhibits insulin secretion

Stable Identifier

R-HSA-400042

DOI

10.3180/R-HSA-400042.5

Type

Pathway

Species

Homo sapiens

Compartment

plasma membrane

ReviewStatus

5/5

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Adrenaline,noradrenaline inhibits insulin secretion

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The catecholamines adrenaline (epinephrine) and noradrenaline (norepinephrine) inhibit insulin secretion from pancreatic beta cells. Four effects are seen in the cells:
1. Inhibition of exocytosis of secretory granules, the major effect.
2. Opening of ATP-sensitive potassium channels (KATP channels) and repolarization of the cell.
3. Closing of L-type voltage-dependent calcium channels and inhibition of calcium influx.
4. Inhibition of adenylyl cyclase activity.
The first event in adrenaline/noradrenaline signaling in beta cells is the binding of adrenaline or noradrenaline to alpha-2 adrenergic receptors, which are G-protein coupled receptors. Binding activates the alpha subunits in heterotrimeric Gi and Go complexes to exchange GDP for GTP, forming the active G alpha:GTP complex. Experiments using specific antibodies against the alpha subunits in mice show that Gi alpha-1, Gi alpha-2, and Go alpha-2 are responsible for adrenergic effects. The exact beta and gamma subunits of the heterotrimeric G-proteins are unknown.
After activation by GTP, the heterotrimeric complex dissociates into the G alpha:GTP complex and the beta:gamma complex. The G alpha:GTP complex causes the inhibition of exocytosis by an unknown mechanism that involves protein acylation. This is responsible for most of the observed inhibition of insulin secretion. Additionally, the G alpha:GTP complex activates (opens) KATP channels, allowing the cell to repolarize. The beta:gamma complex inhibits (closes) voltage-dependent calcium channels, reducing the intracellular calcium concentration, and inhibits adenylyl cyclase, reducing the intracellular cAMP concentration.

Literature References

PubMed ID	Title	Journal	Year
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 Okamoto, T, Regazzi, R, Kiraly, C, Lang, J, Weller, U, Wollheim, CB, Nishimoto, I	EMBO J	1995
8997178	Mechanisms of inhibition of insulin release Sharp, GW	Am J Physiol	1996
14514350	Inhibition of insulin secretion via distinct signaling pathways in alpha2-adrenoceptor knockout mice Chao, CM, Brede, M, Hein, L, Sieg, A, Peterhoff, M, Ullrich, S	Eur J Endocrinol	2003
10449730	Regions on adenylyl cyclase that are necessary for inhibition of activity by beta gamma and G(ialpha) subunits of heterotrimeric G proteins Wittpoth, C, Scholich, K, Yigzaw, Y, Patel, TB, Stringfield, TM	Proc Natl Acad Sci U S A	1999
12684222	Protein acylation in the inhibition of insulin secretion by norepinephrine, somatostatin, galanin, and PGE2 Straub, SG, Sharp, GW, Cheng, H	Am J Physiol Endocrinol Metab	2003
17900700	G-protein-coupled receptors and islet function-implications for treatment of type 2 diabetes Ahren, B, Winzell, MS	Pharmacol Ther	2007
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 Straub, SG, Fang, Q, Sharp, GW, Zhao, Y	J Biol Chem	2008