Activation of Epac2 by cAMP Exchange of GDP for GTP by Rap1A Activation of Epac1 by cAMP Binding of Glucagon-like Peptide-1 by Glucagon-like Peptide-1 Receptor Activation of G(s) by GLP-1R Rearrangement of the heterotrimeric G(s) complex Activation of Adenylyl Cyclase by G(s):GTP Production of Cyclic AMP by Activated Adenylyl Cyclase cAMP induces dissociation of active PKA catalytic subunits from the PKA:AKAP79:IQGAP1 Complex Closing of Potassium voltage-gated channels by PKA Opening of ER calcium channels by activated PKA PathwayStep2048 PathwayStep2047 PathwayStep2049 PathwayStep2050 PathwayStep2046 PathwayStep2045 PathwayStep2044 PathwayStep2043 PathwayStep2042 PathwayStep2041 PathwayStep2040 Regulation of Insulin Secretion by Glucagon-like Peptide-1 Authored: May, B, 2009-05-28 03:42:50 Edited: May, B, 2009-05-28 03:42:50 Glucagon-like Peptide-1 (GLP-1) is secreted by L-cells in the intestine in response to glucose and fatty acids. GLP-1 circulates to the beta cells of the pancreas where it binds a G-protein coupled receptor, GLP-1R, on the plasma membrane. The binding activates the heterotrimeric G-protein G(s), causing the alpha subunit of G(s) to exchange GDP for GTP and dissociate from the beta and gamma subunits.<br>The activated G(s) alpha subunit interacts with Adenylyl Cyclase VIII (Adenylate Cyclase VIII, AC VIII) and activates AC VIII to produce cyclic AMP (cAMP). cAMP then has two effects: 1) cAMP activates Protein Kinase A (PKA), and 2) cAMP activates Epac1 and Epac2, two guanyl nucleotide exchange factors.<br>Binding of cAMP to PKA causes the catalytic subunits of PKA to dissociate from the regulatory subunits and become an active kinase. PKA is known to enhance insulin secretion by closing ATP-sensitive potassium channels, closing voltage-gated potassium channels, releasing calcium from the endoplasmic reticulum, and affecting insulin secretory granules. The exact mechanisms for PKA's action are not fully known. After prolonged increases in cAMP, PKA translocates to the nucleus where it regulates the PDX-1 and CREB transcription factors, activating transcription of the insulin gene.<br>cAMP produced by AC VIII also activates Epac1 and Epac2, which catalyze the exchange of GTP for GDP on G-proteins, notably Rap1A.. Rap1A regulates insulin secretory granules and is believed to activate the Raf/MEK/ERK mitogenic pathway leading to proliferation of beta cells. The Epac proteins also interact with RYR calcium channels on the endoplasmic reticulum, the SUR1 subunits of ATP-sensitive potassium channels, and the Piccolo:Rim2 calcium sensor at the plasma membrane. Pubmed11078440 Pubmed11815463 Pubmed12475787 Pubmed15569269 Pubmed17306374 Pubmed17900700 Pubmed8830891 Pubmed9914469 Reactome Database ID Release 43381676 Reactome, http://www.reactome.org ReactomeREACT_18274 Reviewed: Gillespie, ME, 2009-06-02 00:59:01