Integration of energy metabolism (Homo sapiens)

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9, 15, 6813, 50, 52, 57, 63...13, 27, 37, 52, 69...111, 7, 20, 40, 47...6, 21, 26, 41, 46...20, 49, 97, 105, 121...2, 34, 45, 77, 80...3, 8, 17, 19, 30...13, 52, 67, 90, 91, 129...1, 7, 20, 40, 47...59, 71, 74, 99, 118...11813, 52, 91, 13333, 48, 51, 88, 93...5, 13220, 23, 114, 131, 13620, 78, 115, 133, 136118, 133, 13910, 24, 89, 100, 107...13, 52, 53, 91, 110...5820, 49, 62, 105, 133...20, 61, 110, 115, 133...13, 22, 52, 62, 84...1518, 21, 32, 35, 46...12, 11820, 47, 134, 13610513, 52, 91, 13344, 64, 66, 7925, 36, 42, 43, 82...16, 20, 28, 103, 113...1421424, 20, 86, 13629, 31, 75, 10920, 39, 73, 97, 106...118, 133, 137, 138ChREBPMLX mitochondrial matrixAMPK heterotrimerAMP G betaG gamma transketolase dimer Ligands of FFAR1 G-beta subunit cAMPPKA regulatory subunit G-alphaG-protein i/o alphaGTPG-protein betaG-protein gamma Complex G-betaG-gamma phosphoPFKFB1 dimer GlucagonGCGR Rap1 Adenylate cyclase G-protein alpha Adenylate cyclase Protein Kinase C, alpha type DAG G-protein with GAMPK gamma2AMP GLP-1GLP-1R G-betaG-gamma GLP-1R Heterotrimeric Gsecretory granuleGSNARE Complex G-protein alpha RAPGEF3cAMP complex IP3 receptorIP3 complex G-betaG-gamma Adenylate cyclase cAMPPKA regulatory subunit IP3 receptors G-protein alpha i/oGTP Complex cAMPPKAAKAP79IQGAP1 Complex Alpha-2A/2C Adrenergic Receptors G-protein alpha i/oGDP Complex SUR1-ATP Complex Adrenaline and Noradrenaline PKA tetramer PKA regulatory subunit PKAAKAP79IQGAP1 Complex mature GLP-1 FFAR1fatty acid IP3 receptor homotetramer GRAPGEF4cAMP Complex G-protein alpha PKA regulatory subunit GGLP-1 GLP-1R Heterotrimeric GG-betaG-gamma G-protein alpha PKA catalytic subunit G-betaG-gamma Gs-activated adenylate cyclase PKA tetramer Activated AMPK heterotrimer IP3 receptors PKA catalytic subunit mature GLP-1 Inward Rectifying Potassium Channel G-protein alpha i/oGTP Complex GAdrenaline/NoradrenalineAlpha-2A/2C Adrenergic Receptor Complex AMPK gamma2AMP Rap1-GDP Adenylate cyclase type V or VI G-protein beta gamma Complex G-gamma subunit nucleoplasmG-beta subunit Insulin G-betaG-gamma GAMPK heterotrimer G-protein alpha G-protein alpha GPP2A-ABdeltaC complex PKA regulatory subunit G-betaG-gamma dimer Muscarinic Acetylcholine Receptor M3Acetylcholine Complex G-betaG-gamma G-protein alpha PFKFB1 dimer Rap1 Inactive PP2A-ABdeltaC complex GLP-1 GLP-1R Heterotrimeric GSTX1ASTXBP1 G betaG gamma PKA regulatory subunit Core SNARE Complex G-protein alpha Adenylate cyclase endoplasmic reticulum lumeninsulin IP3 receptor homotetramer cytosolG-gamma subunit G-betaG-gamma dimer PP2A-ABdeltaC complex Insulin-Zinc-Calcium Complex GLP-1GLP-1R Inward Rectifying Potassium Channel G-betaG-gamma G betaG gamma G-protein alpha PLC beta1/2/3GG-protein i/o alphaGDPG-protein betaG-protein gamma Complex InsulinZincCalcium Complex in docked granule Adenylate cyclase Rap1-GTP Mg2+ CHRM3 GLP1R PRKAR2B p-4S-MARCKSZn2+ Gs-activated adenylate cyclasePRKAR2A ADPGLP-1 GLP-1R Heterotrimeric GVAMP2 GNASGTPADRA2C H2OINSVAMP2 RGZ Ca2+ ACCAlpha-2A/2C Adrenergic ReceptorsADCY3 O-phosphopantetheine-L-serine-FASNPKLR-1ACLYPRKAR2A PRKACB GNASGTP GDPPPP2R5D Glucagon GNG11 PKA catalytic subunitGlcG-protein i/o alphaGTPG-protein betaG-protein gamma ComplexITPR1 RAP1A SYT5 STX1ASTXBP1ADCY4 PPP2R5D H2OPotassium Channel, open GNG4 Adrenaline and NoradrenalinePRKAA2 Inward Rectifying Potassium Channel XY5PcAMPPKA regulatory subunitGGTP Ca-channel PLC beta1/2/3G2xHC-INSAcChoABCC8PRKAR1AADCY2 Ligands of FFAR1 G-betaG-gamma ATPADCY4 PRKAG2 GTP GNB1 GNG5 GNB2 OLEA GLP-1 STXBP1 GDPADCY1 Voltage-gated Calcium Channels Type Cav1 RAPGEF3cAMP complexGNG13 GLP-1R Heterotrimeric GADCY6 RAPGEF3 Inactive PP2A-ABdeltaC complexIRAPGEF3ATPGNG12 p-T172-PRKAA2 GNB4 transketolase dimerG-protein i/o alphaGDPG-protein betaG-protein gamma ComplexGNASVAMP2PRKAA2 GNG2 GTP ITPR3 AcCho KCNJ11 GNG13 MLXIPLMLXp-S196,T666-MLXIPLGNG7 PPP2R5D AMPPRKACA PRKCAPALM AGPAT1PRKAG2 ITPR2 GDP PRKAB2 PRKAR1B GA3PPotassium voltage-gated channels PLC beta 1/2/3Muscarinic Acetylcholine Receptor M3Acetylcholine ComplexRAP1A GTP ABCC8 Adrenaline/NoradrenalineAlpha-2A/2C Adrenergic Receptor ComplexADR 3',5'-Cyclic AMPPFKFB1 dimerADCY1 RAPGEF4PP2A-ABdeltaC complexSTX1A E4Pp-T666-MLXIPLSYT5H2OADCY9 ArgN-GCGGDP PRKAR1B G-protein alpha i/oGTP ComplexIP3 receptorIP3 complexGLP1R ADPSTXBP1IQGAP1 ArgN-GCGSedoheptulose 7-phosphateGNASInsulinZincCalcium Complex in docked granuleGlcADPInward Rectifying Potassium Channel ADP/ATP translocase dimerRap1-GDPADCY3 STX1A 4xHC-INSPRKAR1B PRKACA GNASAdenylyl cyclase PFKFB1AKAP5 PRKAR2A AMPK heterotrimerAMPADPCHRM3phosphoPFKFB1 dimerPRKAR2B PRKAG2 Fatty acidsGNG12 p-S33-PFKFB1GNASADPADPITPR2 GNB1 ATPINSGDPActivated AMPK heterotrimerATPNAd Ca2+GTPPRKAB2 GLP1R MLXIPL Rap1-GTPGCGRGNG3 ADRA2A 3',5'-Cyclic AMP GLP-1 2xHC-INSPRKACG IQGAP1 GTP GTPGCa2+3',5'-Cyclic AMP p-T666-MLXIPLADCY8 FFAR1fatty acidDAGAKAP5 Insulin-Zinc-Calcium Complex3',5'-Cyclic AMP PRKCA ThDP RAPGEF4 GCGR Potassium Channel, closed GDPITPR1 Ca-channel PiPPiATPVoltage-gated Calcium Channels Type Cav1 PRKAR1AAdenylate cyclase type V or VI G-protein beta gamma ComplexADCY5 TKT ADCY8 GNG4 PRKAR2A Protein Kinase A, catalytic subunitscAMPPKAAKAP79IQGAP1 ComplexCa2+ GNB2 RAP1B Core SNARE ComplexFFAR1 ADCY5 PRKAR2B 4xHC-INSmature GLP-1Adenylate cyclase GNB3 GNB3 STK11GNG2 G betaG gammaPKAAKAP79IQGAP1 ComplexGTP GNG10 ITPR3 ABCC8 AMPK heterotrimer GNB4 FruGDP PRKAR1ASNAP25GDPPotassium voltage-gated channels GLP-1 GLP-1R Heterotrimeric GMg2+ MLX SNAP25 GNG10 GTP GTP PRKAR1AGNG8PiGTPADPADCY7 RAPGEF4cAMP ComplexGlucagonGCGRPIGDP PRKAR2B GNG11 GNG7 ADCY7 IP3 receptor homotetramerATPG-protein alpha GNG5 PRKACB G-protein with GGDPADCY9 GlucagonGNG8FFAR1GTP RAP1B AMP SNARE ComplexGMARCKSProtein Kinase C, alpha type DAGGTPPRKAB2 G-alphap-S568-MLXIPLAMPR5PPP2A-ABdeltaC complexCa2+Zn2+ PRKACG Adenylate Cyclase V or VIGDP ATPCa2+ KCNJ11 ATPGNG3 Mg2+ STX1A Adenylate cyclase G-protein alpha DAG ATP G-betaG-gamma dimerGNASPKA catalytic subunitPRKAR1B GTP DDCX ADCY6 IChREBPMLXPKA tetramerAMP Pentadecanoic acid GDP 3',5'-Cyclic AMP ADCY2 GLUT1 and GLUT2 GNASGTPTALDO1Voltage-gated Calcium Channels 62, 105621326213014233, 88, 11714114


Description

Many hormones that affect individual physiological processes including the regulation of appetite, absorption, transport, and oxidation of foodstuffs influence energy metabolism pathways. While insulin mediates the storage of excess nutrients, glucagon is involved in the mobilization of energy resources in response to low blood glucose levels, principally by stimulating hepatic glucose output. Small doses of glucagon are sufficient to induce significant glucose elevations. These hormone-driven regulatory pathways enable the body to sense and respond to changed amounts of nutrients in the blood and demands for energy.
Glucagon and Insulin act through various metabolites and enzymes that target specific steps in metabolic pathways for sugar and fatty acids. The processes responsible for the long-term control of fat synthesis and short term control of glycolysis by key metabolic products and enzymes are annotated in this module as six specific pathways:
Pathway 1. Glucagon signalling in metabolic pathways: In response to low blood glucose, pancreatic alpha-cells release glucagon. The binding of glucagon to its receptor results in increased cAMP synthesis, and Protein Kinase A (PKA) activation.
Pathway 2. PKA mediated phosphorylation:PKA phosphorylates key enzymes, e.g., 6-Phosphofructo-2-kinase /Fructose-2,6-bisphosphatase (PF2K-Pase) at serine 36, and regulatory proteins, e.g., Carbohydrate Response Element Binding Protein (ChREBP) at serine 196 and threonine 666.
Insulin mediated responses to high blood glucose will be annotated in future versions of Reactome. In brief, the binding of insulin to its receptor leads to increased protein phosphatase activity and to hydrolysis of cAMP by cAMP phosphodiesterase. These events counteract the regulatory effects of glucagon.
Pathway 3: Insulin stimulates increased synthesis of Xylulose-5-phosphate (Xy-5-P). Activation of the insulin receptor results indirectly in increased Xy-5-P synthesis from Glyceraldehyde-3-phosphate and Fructose-6-phosphate. Xy-5-P, a metabolite of the pentose phosphate pathway, stimulates protein phosphatase PP2A.
Pathway 4: AMP Kinase (AMPK) mediated response to high AMP:ATP ratio: In response to diet with high fat content or low energy levels, the cytosolic AMP:ATP ratio is increased. AMP triggers a complicated cascade of events. In this module we have annotated only the phosphorylation of ChREBP by AMPK at serine 568, which inactivates this transcription factor.
Pathway 5: Dephosphorylation of key metabolic factors by PP2A: Xy-5-P activated PP2A efficiently dephosphorylates phosphorylated PF2K-Pase resulting in the higher output of F-2,6-P2 that enhances PFK activity in the glycolytic pathway. PP2A also dephosphorylates (and thus activates) cytosolic and nuclear ChREBP.
Pathway 6: Transcriptional activation of metabolic genes by ChREBP: Dephosphorylated ChREBP activates the transcription of genes involved in glucose metabolism such as pyruvate kinase, and lipogenic genes such as acetyl-CoA carboxylase, fatty acid synthetase, acyl CoA synthase and glycerol phosphate acyl transferase.
The illustration below summarizes this network of events. Black lines are metabolic reactions, red lines are negative regulatory events, and green lines are positive regulatory events (figure reused with permission from Veech (2003) - Copyright (2003) National Academy of Sciences, U.S.A.). Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=163685

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  82. Tesmer JJ, Sunahara RK, Gilman AG, Sprang SR.; ''Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsalpha.GTPgammaS.''; PubMed Europe PMC Scholia
  83. Kurose H, Regan JW, Caron MG, Lefkowitz RJ.; ''Functional interactions of recombinant alpha 2 adrenergic receptor subtypes and G proteins in reconstituted phospholipid vesicles.''; PubMed Europe PMC Scholia
  84. Nobles M, Benians A, Tinker A.; ''Heterotrimeric G proteins precouple with G protein-coupled receptors in living cells.''; PubMed Europe PMC Scholia
  85. Banno Y, Yada Y, Nozawa Y.; ''Purification and characterization of membrane-bound phospholipase C specific for phosphoinositides from human platelets.''; PubMed Europe PMC Scholia
  86. Schnell S, Schaefer M, Schöfl C.; ''Free fatty acids increase cytosolic free calcium and stimulate insulin secretion from beta-cells through activation of GPR40.''; PubMed Europe PMC Scholia
  87. Runge S, Schimmer S, Oschmann J, Schiødt CB, Knudsen SM, Jeppesen CB, Madsen K, Lau J, Thøgersen H, Rudolph R.; ''Differential structural properties of GLP-1 and exendin-4 determine their relative affinity for the GLP-1 receptor N-terminal extracellular domain.''; PubMed Europe PMC Scholia
  88. Freitas Lima LC, Braga VA, do Socorro de França Silva M, Cruz JC, Sousa Santos SH, de Oliveira Monteiro MM, Balarini CM.; ''Adipokines, diabetes and atherosclerosis: an inflammatory association.''; PubMed Europe PMC Scholia
  89. Kang G, Leech CA, Chepurny OG, Coetzee WA, Holz GG.; ''Role of the cAMP sensor Epac as a determinant of KATP channel ATP sensitivity in human pancreatic beta-cells and rat INS-1 cells.''; PubMed Europe PMC Scholia
  90. Azpiazu I, Akgoz M, Kalyanaraman V, Gautam N.; ''G protein betagamma11 complex translocation is induced by Gi, Gq and Gs coupling receptors and is regulated by the alpha subunit type.''; PubMed Europe PMC Scholia
  91. Wu L, Fritz JD, Powers AC.; ''Different functional domains of GLUT2 glucose transporter are required for glucose affinity and substrate specificity.''; PubMed Europe PMC Scholia
  92. Kubota M, Wakamatsu K.; ''Peptide fragment of the m3 muscarinic acetylcholine receptor activates G(q) but not G(i2).''; PubMed Europe PMC Scholia
  93. Leech CA, Holz GG, Chepurny O, Habener JF.; ''Expression of cAMP-regulated guanine nucleotide exchange factors in pancreatic beta-cells.''; PubMed Europe PMC Scholia
  94. Noushmehr H, D'Amico E, Farilla L, Hui H, Wawrowsky KA, Mlynarski W, Doria A, Abumrad NA, Perfetti R.; ''Fatty acid translocase (FAT/CD36) is localized on insulin-containing granules in human pancreatic beta-cells and mediates fatty acid effects on insulin secretion.''; PubMed Europe PMC Scholia
  95. Lambert NA.; ''Dissociation of heterotrimeric g proteins in cells.''; PubMed Europe PMC Scholia
  96. Wiederkehr A, Wollheim CB.; ''Minireview: implication of mitochondria in insulin secretion and action.''; PubMed Europe PMC Scholia
  97. Del Guerra S, Bugliani M, D'Aleo V, Del Prato S, Boggi U, Mosca F, Filipponi F, Lupi R.; ''G-protein-coupled receptor 40 (GPR40) expression and its regulation in human pancreatic islets: the role of type 2 diabetes and fatty acids.''; PubMed Europe PMC Scholia
  98. Barg S, Eliasson L, Renström E, Rorsman P.; ''A subset of 50 secretory granules in close contact with L-type Ca2+ channels accounts for first-phase insulin secretion in mouse beta-cells.''; PubMed Europe PMC Scholia
  99. Havula E, Hietakangas V.; ''Glucose sensing by ChREBP/MondoA-Mlx transcription factors.''; PubMed Europe PMC Scholia
  100. Nolan CJ, Madiraju MS, Delghingaro-Augusto V, Peyot ML, Prentki M.; ''Fatty acid signaling in the beta-cell and insulin secretion.''; PubMed Europe PMC Scholia
  101. Eason MG, Liggett SB.; ''Chimeric mutagenesis of putative G-protein coupling domains of the alpha2A-adrenergic receptor. Localization of two redundant and fully competent gi coupling domains.''; PubMed Europe PMC Scholia
  102. Tsuboi T, da Silva Xavier G, Holz GG, Jouaville LS, Thomas AP, Rutter GA.; ''Glucagon-like peptide-1 mobilizes intracellular Ca2+ and stimulates mitochondrial ATP synthesis in pancreatic MIN6 beta-cells.''; PubMed Europe PMC Scholia
  103. Lin YW, MacMullen C, Ganguly A, Stanley CA, Shyng SL.; ''A novel KCNJ11 mutation associated with congenital hyperinsulinism reduces the intrinsic open probability of beta-cell ATP-sensitive potassium channels.''; PubMed Europe PMC Scholia
  104. Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno NH, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T.; ''Cloning of adiponectin receptors that mediate antidiabetic metabolic effects.''; PubMed Europe PMC Scholia
  105. Latour MG, Alquier T, Oseid E, Tremblay C, Jetton TL, Luo J, Lin DC, Poitout V.; ''GPR40 is necessary but not sufficient for fatty acid stimulation of insulin secretion in vivo.''; PubMed Europe PMC Scholia
  106. Ma L, Robinson LN, Towle HC.; ''ChREBP*Mlx is the principal mediator of glucose-induced gene expression in the liver.''; PubMed Europe PMC Scholia
  107. Thorens B, Porret A, Bühler L, Deng SP, Morel P, Widmann C.; ''Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor.''; PubMed Europe PMC Scholia
  108. Colville CA, Seatter MJ, Jess TJ, Gould GW, Thomas HM.; ''Kinetic analysis of the liver-type (GLUT2) and brain-type (GLUT3) glucose transporters in Xenopus oocytes: substrate specificities and effects of transport inhibitors.''; PubMed Europe PMC Scholia
  109. Banki K, Halladay D, Perl A.; ''Cloning and expression of the human gene for transaldolase. A novel highly repetitive element constitutes an integral part of the coding sequence.''; PubMed Europe PMC Scholia
  110. Kang G, Joseph JW, Chepurny OG, Monaco M, Wheeler MB, Bos JL, Schwede F, Genieser HG, Holz GG.; ''Epac-selective cAMP analog 8-pCPT-2'-O-Me-cAMP as a stimulus for Ca2+-induced Ca2+ release and exocytosis in pancreatic beta-cells.''; PubMed Europe PMC Scholia
  111. Verghese GM, Johnson JD, Vasulka C, Haupt DM, Stumpo DJ, Blackshear PJ.; ''Protein kinase C-mediated phosphorylation and calmodulin binding of recombinant myristoylated alanine-rich C kinase substrate (MARCKS) and MARCKS-related protein.''; PubMed Europe PMC Scholia
  112. Sher E, Giovannini F, Codignola A, Passafaro M, Giorgi-Rossi P, Volsen S, Craig P, Davalli A, Carrera P.; ''Voltage-operated calcium channel heterogeneity in pancreatic beta cells: physiopathological implications.''; PubMed Europe PMC Scholia
  113. Lang J, Nishimoto I, Okamoto T, Regazzi R, Kiraly C, Weller U, Wollheim CB.; ''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.''; PubMed Europe PMC Scholia
  114. Dessauer CW, Chen-Goodspeed M, Chen J.; ''Mechanism of Galpha i-mediated inhibition of type V adenylyl cyclase.''; PubMed Europe PMC Scholia
  115. Bavec A, Licar A.; ''Functional characterization of N-terminally GFP-tagged GLP-1 receptor.''; PubMed Europe PMC Scholia
  116. Sharp GW.; ''Mechanisms of inhibition of insulin release.''; PubMed Europe PMC Scholia
  117. McIntire WE.; ''Structural determinants involved in the formation and activation of G protein betagamma dimers.''; PubMed Europe PMC Scholia
  118. Gao Z, Young RA, Trucco MM, Greene SR, Hewlett EL, Matschinsky FM, Wolf BA.; ''Protein kinase A translocation and insulin secretion in pancreatic beta-cells: studies with adenylate cyclase toxin from Bordetella pertussis.''; PubMed Europe PMC Scholia
  119. Proks P, Arnold AL, Bruining J, Girard C, Flanagan SE, Larkin B, Colclough K, Hattersley AT, Ashcroft FM, Ellard S.; ''A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes.''; PubMed Europe PMC Scholia
  120. Luvisetto S, Fellin T, Spagnolo M, Hivert B, Brust PF, Harpold MM, Stauderman KA, Williams ME, Pietrobon D.; ''Modal gating of human CaV2.1 (P/Q-type) calcium channels: I. The slow and the fast gating modes and their modulation by beta subunits.''; PubMed Europe PMC Scholia
  121. MacDonald PE, Wang G, Tsuk S, Dodo C, Kang Y, Tang L, Wheeler MB, Cattral MS, Lakey JR, Salapatek AM, Lotan I, Gaisano HY.; ''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.''; PubMed Europe PMC Scholia
  122. Vignali S, Leiss V, Karl R, Hofmann F, Welling A.; ''Characterization of voltage-dependent sodium and calcium channels in mouse pancreatic A- and B-cells.''; PubMed Europe PMC Scholia
  123. Peterhoff M, Sieg A, Brede M, Chao CM, Hein L, Ullrich S.; ''Inhibition of insulin secretion via distinct signaling pathways in alpha2-adrenoceptor knockout mice.''; PubMed Europe PMC Scholia
  124. Digby GJ, Lober RM, Sethi PR, Lambert NA.; ''Some G protein heterotrimers physically dissociate in living cells.''; PubMed Europe PMC Scholia
  125. Babenko AP, Polak M, Cavé H, Busiah K, Czernichow P, Scharfmann R, Bryan J, Aguilar-Bryan L, Vaxillaire M, Froguel P.; ''Activating mutations in the ABCC8 gene in neonatal diabetes mellitus.''; PubMed Europe PMC Scholia
  126. Ferrer J, Benito C, Gomis R.; ''Pancreatic islet GLUT2 glucose transporter mRNA and protein expression in humans with and without NIDDM.''; PubMed Europe PMC Scholia
  127. Seino S, Iwanaga T, Nagashima K, Miki T.; ''Diverse roles of K(ATP) channels learned from Kir6.2 genetically engineered mice.''; PubMed Europe PMC Scholia
  128. Remaury A, Larrouy D, Daviaud D, Rouot B, Paris H.; ''Coupling of the alpha 2-adrenergic receptor to the inhibitory G-protein Gi and adenylate cyclase in HT29 cells.''; PubMed Europe PMC Scholia
  129. Veech RL.; ''A humble hexose monophosphate pathway metabolite regulates short- and long-term control of lipogenesis.''; PubMed Europe PMC Scholia
  130. Arbuckle MI, Kane S, Porter LM, Seatter MJ, Gould GW.; ''Structure-function analysis of liver-type (GLUT2) and brain-type (GLUT3) glucose transporters: expression of chimeric transporters in Xenopus oocytes suggests an important role for putative transmembrane helix 7 in determining substrate selectivity.''; PubMed Europe PMC Scholia
  131. Nakayama T, Penheiter AR, Penheiter SG, Chini EN, Thompson M, Warner DO, Jones KA.; ''Differential effects of volatile anesthetics on M3 muscarinic receptor coupling to the Galphaq heterotrimeric G protein.''; PubMed Europe PMC Scholia
  132. Kang G, Chepurny OG, Malester B, Rindler MJ, Rehmann H, Bos JL, Schwede F, Coetzee WA, Holz GG.; ''cAMP sensor Epac as a determinant of ATP-sensitive potassium channel activity in human pancreatic beta cells and rat INS-1 cells.''; PubMed Europe PMC Scholia
  133. Siu FY, He M, de Graaf C, Han GW, Yang D, Zhang Z, Zhou C, Xu Q, Wacker D, Joseph JS, Liu W, Lau J, Cherezov V, Katritch V, Wang MW, Stevens RC.; ''Structure of the human glucagon class B G-protein-coupled receptor.''; PubMed Europe PMC Scholia
  134. Ross D, Joyner WL.; ''Resting distribution and stimulated translocation of protein kinase C isoforms alpha, epsilon and zeta in response to bradykinin and TNF in human endothelial cells.''; PubMed Europe PMC Scholia
  135. Tesmer VM, Kawano T, Shankaranarayanan A, Kozasa T, Tesmer JJ.; ''Snapshot of activated G proteins at the membrane: the Galphaq-GRK2-Gbetagamma complex.''; PubMed Europe PMC Scholia
  136. Fujiwara K, Maekawa F, Yada T.; ''Oleic acid interacts with GPR40 to induce Ca2+ signaling in rat islet beta-cells: mediation by PLC and L-type Ca2+ channel and link to insulin release.''; PubMed Europe PMC Scholia
  137. Gromada J, Brock B, Schmitz O, Rorsman P.; ''Glucagon-like peptide-1: regulation of insulin secretion and therapeutic potential.''; PubMed Europe PMC Scholia
  138. Kim SJ, Choi WS, Han JS, Warnock G, Fedida D, McIntosh CH.; ''A novel mechanism for the suppression of a voltage-gated potassium channel by glucose-dependent insulinotropic polypeptide: protein kinase A-dependent endocytosis.''; PubMed Europe PMC Scholia
  139. De Vos A, Heimberg H, Quartier E, Huypens P, Bouwens L, Pipeleers D, Schuit F.; ''Human and rat beta cells differ in glucose transporter but not in glucokinase gene expression.''; PubMed Europe PMC Scholia
  140. Tsuboi T, Rutter GA.; ''Insulin secretion by 'kiss-and-run' exocytosis in clonal pancreatic islet beta-cells.''; PubMed Europe PMC Scholia
  141. Cummins MM, O'Mullane LM, Barden JA, Cook DI, Poronnik P.; ''Antisense co-suppression of G(alpha)(q) and G(alpha)(11) demonstrates that both isoforms mediate M(3)-receptor-activated Ca(2+) signalling in intact epithelial cells.''; PubMed Europe PMC Scholia
  142. Calle R, Ganesan S, Smallwood JI, Rasmussen H.; ''Glucose-induced phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS) in isolated rat pancreatic islets.''; PubMed Europe PMC Scholia
  143. Henquin JC, Ishiyama N, Nenquin M, Ravier MA, Jonas JC.; ''Signals and pools underlying biphasic insulin secretion.''; PubMed Europe PMC Scholia
  144. Yamamoto H, Matsumura T, Kugiyama K, Oishi Y, Ogata N, Yasue H, Miyamoto E.; ''The antibody specific for myristoylated alanine-rich C kinase substrate phosphorylated by protein kinase C: activation of protein kinase C in smooth muscle cells in human coronary arteries.''; PubMed Europe PMC Scholia
  145. Runge S, Thøgersen H, Madsen K, Lau J, Rudolph R.; ''Crystal structure of the ligand-bound glucagon-like peptide-1 receptor extracellular domain.''; PubMed Europe PMC Scholia
  146. Trümper J, Ross D, Jahr H, Brendel MD, Göke R, Hörsch D.; ''The Rap-B-Raf signalling pathway is activated by glucose and glucagon-like peptide-1 in human islet cells.''; PubMed Europe PMC Scholia
  147. Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M.; ''Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.''; PubMed Europe PMC Scholia
  148. Tarasov AI, Nicolson TJ, Riveline JP, Taneja TK, Baldwin SA, Baldwin JM, Charpentier G, Gautier JF, Froguel P, Vaxillaire M, Rutter GA.; ''A rare mutation in ABCC8/SUR1 leading to altered ATP-sensitive K+ channel activity and beta-cell glucose sensing is associated with type 2 diabetes in adults.''; PubMed Europe PMC Scholia
  149. Orskov C, Rabenhøj L, Wettergren A, Kofod H, Holst JJ.; ''Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide I in humans.''; PubMed Europe PMC Scholia
  150. MacDonald PE, El-Kholy W, Riedel MJ, Salapatek AM, Light PE, Wheeler MB.; ''The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion.''; PubMed Europe PMC Scholia
  151. Cheng H, Straub SG, Sharp GW.; ''Protein acylation in the inhibition of insulin secretion by norepinephrine, somatostatin, galanin, and PGE2.''; PubMed Europe PMC Scholia
  152. Wittpoth C, Scholich K, Yigzaw Y, Stringfield TM, Patel TB.; ''Regions on adenylyl cyclase that are necessary for inhibition of activity by beta gamma and G(ialpha) subunits of heterotrimeric G proteins.''; PubMed Europe PMC Scholia
  153. Barg S, Rorsman P.; ''Insulin secretion: a high-affinity Ca2+ sensor after all?''; PubMed Europe PMC Scholia
  154. Verhoeven NM, Huck JH, Roos B, Struys EA, Salomons GS, Douwes AC, van der Knaap MS, Jakobs C.; ''Transaldolase deficiency: liver cirrhosis associated with a new inborn error in the pentose phosphate pathway.''; PubMed Europe PMC Scholia
  155. Zhao Y, Fang Q, Straub SG, Sharp GW.; ''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.''; PubMed Europe PMC Scholia
  156. Yang SN, Berggren PO.; ''The role of voltage-gated calcium channels in pancreatic beta-cell physiology and pathophysiology.''; PubMed Europe PMC Scholia
  157. Ma L, Sham YY, Walters KJ, Towle HC.; ''A critical role for the loop region of the basic helix-loop-helix/leucine zipper protein Mlx in DNA binding and glucose-regulated transcription.''; PubMed Europe PMC Scholia
  158. Jiang G, Zhang BB.; ''Glucagon and regulation of glucose metabolism.''; PubMed Europe PMC Scholia
  159. Kotarsky K, Nilsson NE, Flodgren E, Owman C, Olde B.; ''A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs.''; PubMed Europe PMC Scholia
  160. Hamming KS, Soliman D, Matemisz LC, Niazi O, Lang Y, Gloyn AL, Light PE.; ''Coexpression of the type 2 diabetes susceptibility gene variants KCNJ11 E23K and ABCC8 S1369A alter the ATP and sulfonylurea sensitivities of the ATP-sensitive K(+) channel.''; PubMed Europe PMC Scholia
  161. Gautam D, Han SJ, Hamdan FF, Jeon J, Li B, Li JH, Cui Y, Mears D, Lu H, Deng C, Heard T, Wess J.; ''A critical role for beta cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo.''; PubMed Europe PMC Scholia
  162. Doyle ME, Egan JM.; ''Mechanisms of action of glucagon-like peptide 1 in the pancreas.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114967view16:49, 25 January 2021ReactomeTeamReactome version 75
113411view11:48, 2 November 2020ReactomeTeamReactome version 74
112613view15:59, 9 October 2020ReactomeTeamReactome version 73
101529view11:39, 1 November 2018ReactomeTeamreactome version 66
101064view21:21, 31 October 2018ReactomeTeamreactome version 65
100595view19:56, 31 October 2018ReactomeTeamreactome version 64
100144view16:41, 31 October 2018ReactomeTeamreactome version 63
99694view15:10, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99282view12:46, 31 October 2018ReactomeTeamreactome version 62
93853view13:41, 16 August 2017ReactomeTeamreactome version 61
93414view11:23, 9 August 2017ReactomeTeamreactome version 61
86502view09:19, 11 July 2016ReactomeTeamreactome version 56
83173view10:17, 18 November 2015ReactomeTeamVersion54
81543view13:05, 21 August 2015ReactomeTeamVersion53
77011view08:30, 17 July 2014ReactomeTeamFixed remaining interactions
76716view12:08, 16 July 2014ReactomeTeamFixed remaining interactions
76042view10:10, 11 June 2014ReactomeTeamRe-fixing comment source
75751view11:24, 10 June 2014ReactomeTeamReactome 48 Update
75101view14:05, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74748view08:49, 30 April 2014ReactomeTeamReactome46
72912view15:20, 14 December 2013EgonwFixed the Uniprot-TrEMBL data sources.
69896view19:21, 11 July 2013MaintBotupdated to 2013 schema
44859view09:54, 6 October 2011MartijnVanIerselOntology Term : 'energy metabolic pathway' added !
42162view23:28, 4 March 2011MaintBotModified categories
42052view21:53, 4 March 2011MaintBotAutomatic update
39857view05:53, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2xHC-INSProteinP01308 (Uniprot-TrEMBL)
3',5'-Cyclic AMP MetaboliteCHEBI:17489 (ChEBI)
3',5'-Cyclic AMPMetaboliteCHEBI:17489 (ChEBI)
4xHC-INSProteinP01308 (Uniprot-TrEMBL)
ABCC8 ProteinQ09428 (Uniprot-TrEMBL)
ABCC8ProteinQ09428 (Uniprot-TrEMBL)
ACCProteinREACT_11654 (Reactome)
ACLYProteinP53396 (Uniprot-TrEMBL)
ADCY1 ProteinQ08828 (Uniprot-TrEMBL)
ADCY2 ProteinQ08462 (Uniprot-TrEMBL)
ADCY3 ProteinO60266 (Uniprot-TrEMBL)
ADCY4 ProteinQ8NFM4 (Uniprot-TrEMBL)
ADCY5 ProteinO95622 (Uniprot-TrEMBL)
ADCY6 ProteinO43306 (Uniprot-TrEMBL)
ADCY7 ProteinP51828 (Uniprot-TrEMBL)
ADCY8 ProteinP40145 (Uniprot-TrEMBL)
ADCY9 ProteinO60503 (Uniprot-TrEMBL)
ADP/ATP translocase dimerComplexREACT_9306 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
ADR MetaboliteCHEBI:28918 (ChEBI)
ADRA2A ProteinP08913 (Uniprot-TrEMBL)
ADRA2C ProteinP18825 (Uniprot-TrEMBL)
AGPAT1ProteinQ99943 (Uniprot-TrEMBL)
AKAP5 ProteinP24588 (Uniprot-TrEMBL)
AMP MetaboliteCHEBI:16027 (ChEBI)
AMPMetaboliteCHEBI:16027 (ChEBI)
AMPK heterotrimer AMPComplexREACT_4802 (Reactome)
AMPK heterotrimer ComplexREACT_3733 (Reactome)
ATP MetaboliteCHEBI:15422 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
AcCho MetaboliteCHEBI:15355 (ChEBI)
AcChoMetaboliteCHEBI:15355 (ChEBI)
Activated AMPK heterotrimerComplexREACT_5306 (Reactome)
Adenylate Cyclase V or VIProteinREACT_20885 (Reactome)
Adenylate cyclase G-protein alpha ComplexREACT_19025 (Reactome)
Adenylate cyclase ComplexREACT_17689 (Reactome)
Adenylate cyclase type V or VI G-protein beta gamma ComplexComplexREACT_18486 (Reactome)
Adenylyl cyclase ProteinREACT_20747 (Reactome)
Adrenaline and NoradrenalineMetaboliteREACT_19090 (Reactome)
Adrenaline/Noradrenaline Alpha-2A/2C Adrenergic Receptor ComplexComplexREACT_18594 (Reactome)
Alpha-2A/2C Adrenergic ReceptorsProteinREACT_18657 (Reactome)
ArgN-GCGProteinP01275 (Uniprot-TrEMBL) The amide group at the C-terminus is not necessary for biological activity.
CHRM3 ProteinP20309 (Uniprot-TrEMBL)
CHRM3ProteinP20309 (Uniprot-TrEMBL)
Ca-channel ComplexREACT_18712 (Reactome)
Ca-channel ComplexREACT_18978 (Reactome)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
ChREBP MLXComplexREACT_2382 (Reactome)
Core SNARE ComplexComplexREACT_16105 (Reactome)
DAG MetaboliteCHEBI:17815 (ChEBI)
DAGCHEBI:17815 (ChEBI)
DDCX MetaboliteCHEBI:30805 (ChEBI)
E4PMetaboliteCHEBI:16897 (ChEBI)
FFAR1 fatty acidComplexREACT_19781 (Reactome) The Free fatty acid receptor 1 (FFAR1 or GPR40) is located on pancreatic beta cells and binds to medium and long chain fatty acids (fatty acids having more than 12 carbon groups). FFAR1 is a G-protein coupled receptor that is coupled to Gq.
FFAR1 ProteinO14842 (Uniprot-TrEMBL)
FFAR1ProteinO14842 (Uniprot-TrEMBL)
Fatty acidsREACT_3744 (Reactome)
FruMetaboliteCHEBI:15946 (ChEBI)
G beta G gammaComplexREACT_18681 (Reactome)
G-alphaComplexREACT_18711 (Reactome)
G-beta G-gamma ComplexREACT_18827 (Reactome)
G-beta G-gamma dimerComplexREACT_3447 (Reactome)
G-protein alpha ComplexREACT_5470 (Reactome)
G-protein alpha i/o GTP ComplexComplexREACT_18504 (Reactome)
G-protein i/o alpha

GDP G-protein beta

G-protein gamma Complex		ComplexREACT_18744 (Reactome)
G-protein i/o alpha

GTP G-protein beta

G-protein gamma Complex		ComplexREACT_18596 (Reactome)
G-protein with GComplexREACT_5026 (Reactome)
GA3PMetaboliteCHEBI:29052 (ChEBI)
GCGR ProteinP47871 (Uniprot-TrEMBL)
GCGRProteinP47871 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GLP-1 
GLP-1R
Heterotrimeric G		ComplexREACT_18812 (Reactome)
GLP-1 
GLP-1R
Heterotrimeric G		ComplexREACT_18821 (Reactome)
GLP-1 ProteinP01275 (Uniprot-TrEMBL)
GLP-1R Heterotrimeric GComplexREACT_18624 (Reactome)
GLP1R ProteinP43220 (Uniprot-TrEMBL)
GLUT1 and GLUT2 ComplexREACT_21462 (Reactome) Human pancreatic beta cells contain GLUT1 and GLUT2 transporters, with GLUT1 predominant. Rodent beta cells predominantly contain GLUT2, which may account for differences observed in the toxicity of streptozotocin.
GNASProteinP63092 (Uniprot-TrEMBL)
GNB1 ProteinP62873 (Uniprot-TrEMBL)
GNB2 ProteinP62879 (Uniprot-TrEMBL)
GNB3 ProteinP16520 (Uniprot-TrEMBL)
GNB4 ProteinQ9HAV0 (Uniprot-TrEMBL)
GNG10 ProteinP50151 (Uniprot-TrEMBL)
GNG11 ProteinP61952 (Uniprot-TrEMBL)
GNG12 ProteinQ9UBI6 (Uniprot-TrEMBL)
GNG13 ProteinQ9P2W3 (Uniprot-TrEMBL)
GNG2 ProteinP59768 (Uniprot-TrEMBL)
GNG3 ProteinP63215 (Uniprot-TrEMBL)
GNG4 ProteinP50150 (Uniprot-TrEMBL)
GNG5 ProteinP63218 (Uniprot-TrEMBL)
GNG7 ProteinO60262 (Uniprot-TrEMBL)
GNG8ProteinQ9UK08 (Uniprot-TrEMBL)
GComplexREACT_18484 (Reactome)
GComplexREACT_18540 (Reactome)
GComplexREACT_18564 (Reactome)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
GlcMetaboliteCHEBI:17925 (ChEBI)
Glucagon GCGRComplexREACT_3602 (Reactome)
Glucagon ProteinP01275 (Uniprot-TrEMBL)
GlucagonProteinP01275 (Uniprot-TrEMBL)
Gs-activated adenylate cyclaseComplexREACT_2537 (Reactome)
H2OMetaboliteCHEBI:15377 (ChEBI)
IMetaboliteCHEBI:16595 (ChEBI)
INSProteinP01308 (Uniprot-TrEMBL)
IP3 receptor IP3 complexComplexREACT_12249 (Reactome)
IP3 receptor homotetramerComplexREACT_12247 (Reactome)
IQGAP1 ProteinP46940 (Uniprot-TrEMBL)
ITPR1 ProteinQ14643 (Uniprot-TrEMBL)
ITPR2 ProteinQ14571 (Uniprot-TrEMBL)
ITPR3 ProteinQ14573 (Uniprot-TrEMBL)
Inactive PP2A-ABdeltaC complexComplexREACT_4092 (Reactome)
Insulin

Zinc

Calcium Complex in docked granule		ComplexREACT_17297 (Reactome)
Insulin-Zinc-Calcium ComplexComplexREACT_15636 (Reactome)
Inward Rectifying Potassium Channel ComplexREACT_17204 (Reactome)
Inward Rectifying Potassium Channel ComplexREACT_18063 (Reactome)
KCNJ11 ProteinQ14654 (Uniprot-TrEMBL)
Ligands of FFAR1 MetaboliteREACT_20176 (Reactome)
MARCKSProteinP29966 (Uniprot-TrEMBL)
MLX ProteinQ9UH92 (Uniprot-TrEMBL)
MLXIPL ProteinQ9NP71 (Uniprot-TrEMBL)
MLXIPLProteinQ9NP71 (Uniprot-TrEMBL)
MLXProteinQ9UH92 (Uniprot-TrEMBL)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
Muscarinic Acetylcholine Receptor M3 Acetylcholine ComplexComplexREACT_18706 (Reactome)
NAd MetaboliteCHEBI:18357 (ChEBI)
O-phosphopantetheine-L-serine-FASNProteinP49327 (Uniprot-TrEMBL)
OLEA MetaboliteCHEBI:16196 (ChEBI)
PALM MetaboliteCHEBI:15756 (ChEBI)
PFKFB1 dimerComplexREACT_2587 (Reactome)
PFKFB1ProteinP16118 (Uniprot-TrEMBL)
PIMetaboliteCHEBI:18348 (ChEBI)
PKA

AKAP79

IQGAP1 Complex		ComplexREACT_18813 (Reactome)
PKA catalytic subunitProteinREACT_3031 (Reactome)
PKA tetramerComplexREACT_5749 (Reactome)
PKLR-1ProteinP30613-1 (Uniprot-TrEMBL)
PLC beta 1/2/3ProteinREACT_18548 (Reactome) Pancreatic beta cells contain PLC Beta 1, PLC Beta 2, and PLC Beta 3. It is unknown which PLC or combination of PLC's are activated in response to G(q).
PLC beta1/2/3 GComplexREACT_18449 (Reactome)
PP2A-ABdeltaC complexComplexREACT_2369 (Reactome)
PP2A-ABdeltaC complexComplexREACT_5648 (Reactome)
PPP2R5D ProteinQ14738 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
PRKAA2 ProteinP54646 (Uniprot-TrEMBL)
PRKAB2 ProteinO43741 (Uniprot-TrEMBL)
PRKACA ProteinP17612 (Uniprot-TrEMBL)
PRKACB ProteinP22694 (Uniprot-TrEMBL)
PRKACG ProteinP22612 (Uniprot-TrEMBL)
PRKAG2 ProteinQ9UGJ0 (Uniprot-TrEMBL)
PRKAR1AProteinP10644 (Uniprot-TrEMBL)
PRKAR1B ProteinP31321 (Uniprot-TrEMBL)
PRKAR2A ProteinP13861 (Uniprot-TrEMBL)
PRKAR2B ProteinP31323 (Uniprot-TrEMBL)
PRKCA ProteinP17252 (Uniprot-TrEMBL)
PRKCAProteinP17252 (Uniprot-TrEMBL)
Pentadecanoic acid MetaboliteCHEBI:42504 (ChEBI)
PiMetaboliteCHEBI:18367 (ChEBI)
Potassium Channel, closed REACT_21231 (Reactome)
Potassium Channel, open REACT_20980 (Reactome)
Potassium voltage-gated channels ProteinREACT_18467 (Reactome) Human pancreatic beta cells contain Kv2.1, Kv3.2, Kv6.2, and Kv9.3 voltage gated potassium channels. The channels are closed in a resting beta and channels open in response to depolarization. Open channels counteract the effect of closed ATP-gated potassium channels and thereby end stimulation of insulin secretion .
Potassium voltage-gated channels ProteinREACT_18949 (Reactome) Human pancreatic beta cells contain Kv2.1, Kv3.2, Kv6.2, and Kv9.3 voltage gated potassium channels. The channels are closed in a resting beta and channels open in response to depolarization. Open channels counteract the effect of closed ATP-gated potassium channels and thereby end stimulation of insulin secretion .
Protein Kinase A, catalytic subunitsProteinREACT_2480 (Reactome)
Protein Kinase C, alpha type DAGComplexREACT_18539 (Reactome)
R5PMetaboliteCHEBI:17797 (ChEBI)
RAP1A ProteinP62834 (Uniprot-TrEMBL)
RAP1B ProteinP61224 (Uniprot-TrEMBL)
RAPGEF3 cAMP complexComplexREACT_18906 (Reactome)
RAPGEF3 ProteinO95398 (Uniprot-TrEMBL)
RAPGEF3ProteinO95398 (Uniprot-TrEMBL)
RAPGEF4 cAMP ComplexComplexREACT_18747 (Reactome)
RAPGEF4 ProteinQ8WZA2 (Uniprot-TrEMBL)
RAPGEF4ProteinQ8WZA2 (Uniprot-TrEMBL)
RGZ MetaboliteCHEBI:50122 (ChEBI)
Rap1-GDPComplexREACT_15771 (Reactome)
Rap1-GTPComplexREACT_16044 (Reactome)
SNAP25 ProteinP60880 (Uniprot-TrEMBL)
SNAP25ProteinP60880 (Uniprot-TrEMBL)
SNARE ComplexComplexREACT_15643 (Reactome)
STK11ProteinQ15831 (Uniprot-TrEMBL)
STX1A STXBP1ComplexREACT_16057 (Reactome)
STX1A ProteinQ16623 (Uniprot-TrEMBL)
STXBP1 ProteinP61764 (Uniprot-TrEMBL)
STXBP1ProteinP61764 (Uniprot-TrEMBL)
SYT5 ProteinO00445 (Uniprot-TrEMBL)
SYT5ProteinO00445 (Uniprot-TrEMBL)
Sedoheptulose 7-phosphateMetaboliteCHEBI:15721 (ChEBI)
TALDO1ProteinP37837 (Uniprot-TrEMBL)
TKT ProteinP29401 (Uniprot-TrEMBL)
ThDP MetaboliteCHEBI:9532 (ChEBI)
VAMP2 ProteinP63027 (Uniprot-TrEMBL)
VAMP2ProteinP63027 (Uniprot-TrEMBL)
Voltage-gated Calcium Channels ComplexREACT_17848 (Reactome)
Voltage-gated Calcium Channels Type Cav1 ComplexREACT_18725 (Reactome)
Voltage-gated Calcium Channels Type Cav1 ComplexREACT_19083 (Reactome)
XY5PMetaboliteCHEBI:16332 (ChEBI)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
cAMP

PKA AKAP79

IQGAP1 Complex		ComplexREACT_18785 (Reactome)
cAMP PKA regulatory subunitComplexREACT_4571 (Reactome)
mature GLP-1ProteinREACT_19088 (Reactome)
p-4S-MARCKSProteinP29966 (Uniprot-TrEMBL)
p-S196,T666-MLXIPLProteinQ9NP71 (Uniprot-TrEMBL)
p-S33-PFKFB1ProteinP16118 (Uniprot-TrEMBL)
p-S568-MLXIPLProteinQ9NP71 (Uniprot-TrEMBL)
p-T172-PRKAA2 ProteinP54646 (Uniprot-TrEMBL)
p-T666-MLXIPLProteinQ9NP71 (Uniprot-TrEMBL)
phosphoPFKFB1 dimerComplexREACT_3400 (Reactome)
transketolase dimerComplexREACT_3387 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
3',5'-Cyclic AMPArrowREACT_1292 (Reactome)
3',5'-Cyclic AMPArrowREACT_18321 (Reactome)
3',5'-Cyclic AMPREACT_1532 (Reactome)
3',5'-Cyclic AMPREACT_18272 (Reactome)
3',5'-Cyclic AMPREACT_18315 (Reactome)
3',5'-Cyclic AMPREACT_18397 (Reactome)
ABCC8REACT_16883 (Reactome)
ADP/ATP translocase dimerREACT_9011 (Reactome)
ADPArrowREACT_1325 (Reactome)
ADPArrowREACT_18263 (Reactome)
ADPArrowREACT_2128 (Reactome)
ADPArrowREACT_304 (Reactome)
ADPArrowREACT_349 (Reactome)
ADPArrowREACT_483 (Reactome)
ADPArrowREACT_9011 (Reactome)
ADPREACT_9011 (Reactome)
AMPK heterotrimer AMPREACT_1325 (Reactome)
AMPK heterotrimer REACT_627 (Reactome)
AMPREACT_627 (Reactome)
AMPTBarREACT_349 (Reactome)
ATPArrowREACT_9011 (Reactome)
ATPREACT_1325 (Reactome)
ATPREACT_16883 (Reactome)
ATPREACT_18263 (Reactome)
ATPREACT_2128 (Reactome)
ATPREACT_304 (Reactome)
ATPREACT_349 (Reactome)
ATPREACT_483 (Reactome)
ATPREACT_9011 (Reactome)
AcChoREACT_18428 (Reactome)
Activated AMPK heterotrimerArrowREACT_1325 (Reactome)
Activated AMPK heterotrimerREACT_349 (Reactome)
Adenylate Cyclase V or VIREACT_18261 (Reactome)
Adenylate cyclase G-protein alpha REACT_18321 (Reactome)
Adenylate cyclase REACT_2219 (Reactome)
Adenylyl cyclase REACT_18332 (Reactome)
Adrenaline and NoradrenalineREACT_18370 (Reactome)
Adrenaline/Noradrenaline Alpha-2A/2C Adrenergic Receptor ComplexArrowREACT_18311 (Reactome)
Alpha-2A/2C Adrenergic ReceptorsREACT_18370 (Reactome)
CHRM3REACT_18428 (Reactome)
Ca2+REACT_15326 (Reactome)
ChREBP MLXArrowREACT_1577 (Reactome)
ChREBP MLXArrowREACT_1891 (Reactome)
ChREBP MLXArrowREACT_229 (Reactome)
ChREBP MLXArrowREACT_355 (Reactome)
ChREBP MLXArrowREACT_787 (Reactome)
Core SNARE ComplexREACT_15326 (Reactome)
DAGArrowREACT_18383 (Reactome)
DAGREACT_18303 (Reactome)
E4PArrowREACT_1730 (Reactome)
E4PREACT_1272 (Reactome)
FFAR1 fatty acidREACT_19346 (Reactome)
FFAR1REACT_19366 (Reactome)
Fatty acidsArrowREACT_349 (Reactome)
FruREACT_1272 (Reactome)
FruREACT_1730 (Reactome)
G beta G gammaArrowREACT_18316 (Reactome)
G-beta G-gamma ArrowREACT_18280 (Reactome)
G-beta G-gamma ArrowREACT_18349 (Reactome)
G-beta G-gamma ArrowREACT_18433 (Reactome)
G-beta G-gamma REACT_18261 (Reactome)
G-beta G-gamma dimerArrowREACT_22110 (Reactome)
G-protein alpha ArrowREACT_18433 (Reactome)
G-protein alpha ArrowREACT_22110 (Reactome)
G-protein alpha REACT_18332 (Reactome)
G-protein alpha REACT_2219 (Reactome)
G-protein alpha i/o GTP ComplexArrowREACT_18349 (Reactome)
G-protein alpha i/o GTP ComplexArrowREACT_18430 (Reactome)
G-protein alpha i/o GTP ComplexTBarREACT_15326 (Reactome)
G-protein i/o alpha

GDP G-protein beta

G-protein gamma Complex		REACT_18311 (Reactome)
G-protein i/o alpha

GTP G-protein beta

G-protein gamma Complex		ArrowREACT_18311 (Reactome)
G-protein with GREACT_22110 (Reactome)
GA3PArrowREACT_1272 (Reactome)
GA3PREACT_1450 (Reactome)
GA3PREACT_1730 (Reactome)
GArrowREACT_18309 (Reactome)
GArrowREACT_18316 (Reactome)
GArrowREACT_19346 (Reactome)
GCGRREACT_156 (Reactome)
GDPArrowREACT_18309 (Reactome)
GDPArrowREACT_18311 (Reactome)
GDPArrowREACT_18379 (Reactome)
GDPArrowREACT_18411 (Reactome)
GDPArrowREACT_19346 (Reactome)
GDPArrowREACT_22110 (Reactome)
GLP-1 
GLP-1R
Heterotrimeric G		ArrowREACT_18411 (Reactome)
GLP-1 
GLP-1R
Heterotrimeric G		REACT_18411 (Reactome)
GLP-1R Heterotrimeric GREACT_18260 (Reactome)
GLUT1 and GLUT2 REACT_21415 (Reactome)
GREACT_18309 (Reactome)
GREACT_18418 (Reactome)
GREACT_19346 (Reactome)
GTPREACT_18309 (Reactome)
GTPREACT_18311 (Reactome)
GTPREACT_18379 (Reactome)
GTPREACT_18411 (Reactome)
GTPREACT_19346 (Reactome)
GTPREACT_22110 (Reactome)
Glucagon GCGRREACT_22110 (Reactome)
GlucagonREACT_156 (Reactome)
Gs-activated adenylate cyclaseREACT_1292 (Reactome)
H2OREACT_1347 (Reactome)
H2OREACT_18383 (Reactome)
IArrowREACT_12074 (Reactome)
IArrowREACT_18383 (Reactome)
INSArrowREACT_15326 (Reactome)
INSREACT_15326 (Reactome)
IP3 receptor IP3 complexREACT_12074 (Reactome)
IP3 receptor homotetramerREACT_12008 (Reactome)
IREACT_12008 (Reactome)
Insulin

Zinc

Calcium Complex in docked granule		REACT_15326 (Reactome)
Insulin-Zinc-Calcium ComplexArrowREACT_15326 (Reactome)
Inward Rectifying Potassium Channel REACT_16883 (Reactome)
Ligands of FFAR1 REACT_19366 (Reactome)
MARCKSREACT_18263 (Reactome)
MLXIPLArrowREACT_382 (Reactome)
MLXIPLArrowREACT_814 (Reactome)
MLXIPLREACT_129 (Reactome)
MLXIPLREACT_304 (Reactome)
MLXIPLREACT_349 (Reactome)
MLXREACT_129 (Reactome)
Muscarinic Acetylcholine Receptor M3 Acetylcholine ComplexREACT_18309 (Reactome)
PFKFB1 dimerArrowREACT_1347 (Reactome)
PFKFB1 dimerREACT_2128 (Reactome)
PIREACT_18383 (Reactome)
PKA

AKAP79

IQGAP1 Complex		REACT_18397 (Reactome)
PKA catalytic subunitArrowREACT_1532 (Reactome)
PKA catalytic subunitArrowREACT_16883 (Reactome)
PKA catalytic subunitArrowREACT_18269 (Reactome)
PKA catalytic subunitArrowREACT_18395 (Reactome)
PKA catalytic subunitArrowREACT_18397 (Reactome)
PKA catalytic subunitREACT_2128 (Reactome)
PKA catalytic subunitREACT_483 (Reactome)
PKA tetramerREACT_1532 (Reactome)
PLC beta 1/2/3REACT_18418 (Reactome)
PLC beta1/2/3 GREACT_18383 (Reactome)
PP2A-ABdeltaC complexREACT_1347 (Reactome)
PP2A-ABdeltaC complexREACT_1416 (Reactome)
PP2A-ABdeltaC complexREACT_382 (Reactome)
PP2A-ABdeltaC complexREACT_814 (Reactome)
PPiArrowREACT_1292 (Reactome)
PPiArrowREACT_18321 (Reactome)
PRKCAREACT_18303 (Reactome)
PiArrowREACT_1347 (Reactome)
PiArrowREACT_1416 (Reactome)
PiArrowREACT_382 (Reactome)
PiArrowREACT_814 (Reactome)
Potassium Channel, open TBarREACT_15326 (Reactome)
Protein Kinase A, catalytic subunitsREACT_304 (Reactome)
Protein Kinase C, alpha type DAGREACT_18263 (Reactome)
R5PArrowREACT_1450 (Reactome)
RAPGEF3 cAMP complexArrowREACT_16883 (Reactome)
RAPGEF3 cAMP complexArrowREACT_18379 (Reactome)
RAPGEF3REACT_18315 (Reactome)
RAPGEF4 cAMP ComplexArrowREACT_16883 (Reactome)
RAPGEF4 cAMP ComplexArrowREACT_18379 (Reactome)
RAPGEF4REACT_18272 (Reactome)
REACT_12008 (Reactome) The IP3 receptor (IP3R) is an IP3-gated calcium channel. It is a large, homotetrameric protein, similar to other calcium channel proteins such as ryanodine. The four subunits form a 'four-leafed clover' structure arranged around the central calcium channel. Binding of ligands such as IP3 results in conformational changes in the receptor's structure that leads to channel opening.
REACT_12074 (Reactome) IP3 promotes the release of intracellular calcium.
REACT_1272 (Reactome) Cytosolic transaldolase (TALDO1) catalyzes the reversible reaction of D-erythrose 4-phosphate and D-fructose 6-phosphate to form D-glyceraldehyde 3-phosphate and sedoheptulose 7-phosphate. Protein expressed from the cloned gene has been characterized biochemically (Banki et al. 1994) and transaldolase deficiency in a patient has been correlated with a mutation in the TALDO1 gene (Verhoeven et al. 2001).
REACT_1292 (Reactome) Activated adenylate cyclase associated with the plasma membrane catalyzes the reaction of cytosolic ATP to form 3',5'-cyclicAMP and pyrophosphate.
REACT_129 (Reactome) At the beginning of this reaction, 1 molecule of 'ChREBP protein', and 1 molecule of 'MLX protein' are present. At the end of this reaction, 1 molecule of 'ChREBP:MLX' is present.

This reaction takes place in the 'nucleus'.

REACT_1310 (Reactome) ChREBP (Carbohydrate Response Element Binding Protein) doubly phosphorylated at threonine 666 and serine 196 is inactive and is localized to the cytosol. Removal of the phosphate residue at serine 196 allows ChREBP to translocate between the cytosol and the nucleoplasm.
REACT_1325 (Reactome) LKB1 phosphorylates threonine residue 172 of the alpha subunit of the AMPK heterotrimer, activating it. LKB1, a serine/threonine kinase, was first identified as the gene whose mutation is associated with the Peutz-Jeghers familial cancer syndrome. This disease phenotype is consistent with the hypothesis that the interaction between LKB1 and AMPK normally plays a key role in the negative regulation of cell growth (Hardie 2004).
REACT_1347 (Reactome) At the beginning of this reaction, 1 molecule of 'pPF2K-Pase complex' is present. At the end of this reaction, 1 molecule of 'Orthophosphate', and 1 molecule of 'PF2K-Pase1 homodimer' are present.

This reaction takes place in the 'cytosol' and is mediated by the 'phosphatidate phosphatase activity' of 'PP2A-ABdeltaC complex'.

REACT_1416 (Reactome) At the beginning of this reaction, 1 molecule of 'pChREBP (Ser 196, Thr 666)' is present. At the end of this reaction, 1 molecule of 'Orthophosphate', and 1 molecule of 'pChREBP (Thr 666)' are present.

This reaction takes place in the 'cytosol' and is mediated by the 'phosphatidate phosphatase activity' of 'PP2A-ABdeltaC complex'.

REACT_1450 (Reactome) Cytosolic transketolase catalyzes the reversible reaction of D-glyceraldehyde 3-phosphate and sedoheptulose 7-phosphate to form D-xylulose 5-phosphate and D-ribose 5-phosphate. The active transketolase enzyme is a homodimer with one molecule of thiamine pyrophosphate and magnesium bound to each monomer (Wang et al. 1997).
REACT_15326 (Reactome) 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.

REACT_1532 (Reactome) The four protein kinase A (PKA) regulatory subunit isoforms differ in their tissue specificity and functional characteristics. The specific isoform activated in response to glucagon signalling is not known. The PKA kinase is a tetramer of two regulatory and two catalytic. The regulatory subunits block the catalytic subunits. Binding of cAMP to the regulatory subunit leads to the dissociation of the tetramer into two active dimers made up of a regulatory and a catalytic subunit.
REACT_156 (Reactome) Glucagon (Thomsen J et al, 1972) is an important peptide hormone produced by the pancreas. It is released when the glucose level in the blood is low (hypoglycemia), causing the liver to convert stored glycogen into glucose and release it into the bloodstream. The action of glucagon is thus opposite to that of insulin. Glucagon, together with glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2), are peptide hormones encoded by a single common prohormone precursor, proglucagon.The glucagon receptor (Lok S et al, 1994) plays a central role in regulating the level of blood glucose by controlling the rate of hepatic glucose production and insulin secretion. The activity of this receptor is mediated by coupling to Gs and q, which stimulate adenylyl cyclase and a phosphatidylinositol-calcium second messenger system respectively.
REACT_1577 (Reactome) At the end of this reaction, 1 molecule of 'citrate lyase monomer' is present.

This reaction takes place in the 'nucleus'.

REACT_16883 (Reactome) ATP-sensitive potassium channels (KATP channels) bind ATP and close. The KATP channels in the beta cell are inward rectifying (allowing potassium ions to pass out the cell) and are partially responsible for maintaining the resting potential of the cell, about -70 mV. Closure of the KATP channels causes a depolarization (a reduction in the voltage differential) across the plasma membrane.
REACT_16913 (Reactome) Voltage-gated calcium channels respond to a change in voltage across the plasma membrane by opening and allowing free movement of calcium ions. In an unstimulated cell the concentration of calcium ions outside the cells is higher than inside due to calcium transporters so channel opening results in an influx of calcium into the cytosol. In the cytosol the calcium ions cause an immediate exocytosis of the readily releasable pool of docked insulin granules as well as a migration of reserve granules toward the plasma membrane where they will be released during the second, sustained phase of insulin secretion.
Mouse and human beta cells are known to contain L type channels Cav1.2 and Cav1.3, both of which have been shown to physically associate with docked insulin granules via Syntaxin1A. Cav1.2 and Cav1.3 predominate in the initial rapid release of insulin. Human beta cells also contain the P/Q type channel Cav2.1 and the R type channel Cav2.3. Cav2.3 is involved in regulating the second, sustained phase of insulin release but signaling and regulatory differences between the two phases of secretion are not fully characterized. Human cells also exhibit T-type (brief burst) calcium currents but the responsible channel has not been identified.
REACT_1730 (Reactome) Cytosolic transketolase catalyzes the reaction of D-glyceraldehyde 3-phosphate and D-fructose 6-phosphate to form D-erythrose 4-phosphate and D-xylulose 5-phosphate. The active transketolase enzyme is a homodimer with one molecule of thiamine pyrophosphate and magnesium bound to each monomer (Wang et al. 1997).
REACT_18260 (Reactome) Glucagon-like Peptide-1 is synthesized in intestinal L-cells in response to the presence of glucose and fatty acids absorbed from the intestine. Most GLP-1 is the GLP-1 (7-36) amidated form; some GLP-1 is the GLP-1 (7-37) form. GLP-1 circulates to the pancreas where it binds the Glucagon-like Peptide-1 Receptor (GLP-1R), a G-protein coupled receptor located on the plasma membrane of beta cells. GLP-1R is a seven-pass transmembrane protein and a member of the B family of GPCRs, which have N-terminal extracellular domains of 100-150 amino acids. GLP-1 interacts with the extracellular N-terminal region of GLP-1R.
REACT_18261 (Reactome) Adenylyl cyclases V and VI are the particular adenylyl cyclases present in beta cells of the human pancreas. The G-protein beta-gamma complex interacts with adenylyl cyclases via protein-protein interactions with the C1 and C2 cytoplasmic loops of adenylyl cyclase. The interaction may produce either stimulation or inhibition of the adenylyl cyclase depending on the particular adenylyl cyclase. In the case of adenylyl cyclases V and VI the interaction inhibits cyclase activity.
REACT_18263 (Reactome) One of the known targets of PKC-alpha is the Myristoylated Alanine-rich C Kinase Substrate (MARCKS). MARCKS is phosphorylated at 4 serine residues and is believed to affect trafficking of insulin granules, increasing insulin secretion.
REACT_18269 (Reactome) Protein kinase A acts to antagonize voltage-gated potassium channels (Kv channels) by increasing the polarizing voltage required to open them. Maintenance of the Kv channels in the closed state prolongs depolarization and insulin secretion. The exact mechanism of the interaction between PKA and the Kv channels is unknown.
REACT_18272 (Reactome) Each molecule of Epac2 binds 2 molecules of cAMP. Epac2 binds cAMP less tightly than PKA binds cAMP so it is believed that Epac2 binds cAMP after PKA is saturated. The binding of cAMP by Epac2 activates the guanyl nucleotide exchange activity of Epac2. Epac2 has also been shown to directly bind the SUR1 subunits of ATP-gated potassium channels (KATP channels) in beta cells so Epac2 may regulate potassium transport.
Epac2 interacts with the calcium sensor Piccolo in a complex with Rim2 at the cell membrane. This may influence exocytosis of insulin. Epac2 also interacts with the ryanodine-sensitive calcium channel on the ER membrane and may cause release of calcium from the ER into the cytosol.
REACT_18280 (Reactome) Closing (inhibition) of the L-type calcium channels in the plasma membrane prevents the flow of calcium ions across the membrane.
REACT_18303 (Reactome) Diacylglycerol, produced by PLC beta-mediated PIP2 hydrolysis in G alpha (q) signalling, remains in the plasma membrane and binds Protein Kinase C alpha (PKC-alpha), causing PKC-alpha to translocate from the cytosol to the plasma membrane. PKC-alpha is thereby activated and phosphorylates target proteins.
REACT_18309 (Reactome) The binding of acetylcholine to the Muscarinic Acetylcholine Receptor M3 activates the heterotrimeric G protein, Gq, associated with the M3 receptor. Activation occurs through protein-protein interaction and results in the alpha subunit of Gq exchanging GDP for GTP (i.e releasing GDP and binding GTP). The 3 subunits of the G protein then dissociate into an alpha:GTP complex and a beta:gamma complex.
REACT_18311 (Reactome) In the pancreatic beta cell, alpha2 adrenergic receptors are coupled to Gi and Go heterotrimeric G-proteins. Binding of adrenaline or noradrenaline by the alpha2 adrenergic receptor acts through protein-protein interaction to stimulate the Gi alpha subunit or Go alpha subunit in heterotrimeric G-protein complexes to exchange GDP for GTP. The particular G alpha subunits have been identified in mice as Gi alpha1, Gi alpha 2, and Go alpha2.
REACT_18315 (Reactome) Each molecule of Epac1 binds 1 molecule of cAMP. Epac1 binds cAMP less tightly than PKA binds cAMP so it is believed that Epac1 binds cAMP after PKA is saturated. The binding of cAMP by Epac1 activates the guanyl nucleotide exchange activity of Epac1. Epac1 has also been shown to bind the SUR1 subunit of ATP-gated potassium channels (KATP channels) in beta cells so Epac1 may participate in direct regulation of potassium transport.
Epac1 also interacts with the calcium sensor Piccolo in a complex with Rim2 at the cell membrane. This may influence exocytosis of insulin.
REACT_18316 (Reactome) In the non-activated state heterotrimeric G proteins exist at membranes as heterotrimeric complexes of alpha, beta, and gamma subunits, with the alpha subunit bound to GDP. Upon activation by a receptor coupled to the heterotrimer, exchange of GDP for GTP by the Gq alpha subunit causes the alpha subunit to lose affinity for the beta and gamma subunits. The alpha subunit with bound GTP then dissociates from the beta and gamma subunits.
REACT_18321 (Reactome) Activated adenylyl cyclase catalyzes the conversion of one molecule of ATP to one molecule of 3',5'-cyclic AMP (cAMP) and one molecule of pyrophosphate.
REACT_18332 (Reactome) By analogy with adenylyl cyclases I and II, adenylyl cyclase VIII is activated by G(s) alpha:GTP by protein-protein interaction between G(s) alpha and the C2 region of adenylyl cyclase VIII, forming a complex. Adenylyl cyclase VIII is present in beta cells of rat and is activated by both G(s) alpha:GTP and calcium:calmodulin, thus integrating signals from both GLP-1 via G(s) alpha and glucose via calcium. Human beta cells contain adenylyl cyclases V and VI, which are also activated by G(s) alpha:GTP, and may contain additional adenylyl cyclases.
REACT_18349 (Reactome) Exchange of GDP for GTP by the alpha subunit of the heterotrimeric G-protein complex causes the complex to dissociate into the G alpha:GTP complex and the beta-gamma complex. Both complexes have effector functions.
REACT_18370 (Reactome) The pancreatic beta cell contains Alpha2A and Alpha2C Adrenergic Receptors. These are G-protein coupled receptors that can bind either adrenaline or noradrenaline.
REACT_18379 (Reactome) Epac1 and Epac2 are activated by binding cAMP and positively regulate the exchange of GDP for GTP by the small GTPase Rap1A. The downstream effects of Rap1A:GTP in beta cells are uncertain but may involve increasing the number of "restless newcomer" secretory granules near the plasma membrane and thereby increasing secretion of insulin.
Other effects of Rap1A :GTP may include regulating beta cell proliferation through activation of the Raf/MEK/ERK mitogenic cascade and activation of the PI3 Kinase/PDK/PKC cell growth pathway.
REACT_18383 (Reactome) Phospholipase C beta-1 associated with the G(q) complex in the plasma membrane catalyzes the hydrolysis of 1-Phosphatidyl-D-myo-inositol 4,5-bisphosphate to yield D-myo-Inositol 1,4,5-trisphosphate and 1,2-Diacylglycerol.
REACT_18395 (Reactome) Activated Protein Kinase A promotes the release of calcium from the endoplasmic reticulum into the cytosol. This may be due to phosphorylation of ER calcium channels by PKA, however this has not been demonstrated.
REACT_18397 (Reactome) The inactive Protein Kinase A (PKA) complex contains 2 regulatory subunits and 2 catalytic subunits. Binding of the regulatory subunits to the catalytic subunits maintains inactivity. In humans there are 3 different catalytic subunits and 4 different regulatory subunits. The particular subunits present in the beta cells of the pancreas are unknown. In beta cells PKA is associated with AKAP79 and IQGAP1, which are believed to tether PKA to the inner surface of the plasma membrane.
Activation by cAMP occurs when each regulatory subunit binds 2 molecules of cAMP, causing dissociation of the catalytic subunits. The active catalytic subunits are thereby released to phosphorylate their target proteins.
Prolonged exposure to increased cAMP levels results in translocation of the active catalytic subunits to the nucleus, where they regulate the PDX-1 and CREB transcription factors and cause increased transcription of the insulin gene.
REACT_18411 (Reactome) GLP-1R that has bound GLP-1 activates the alpha subunit of the heterotrimeric G-protein G(s) by protein-protein interaction between intracellular loop 3 of GLP-1R and G(s). The activation causes exchange of GDP for GTP by the alpha subunit of G(s).
REACT_18418 (Reactome) The Gq alpha:GTP complex activates Phospholipase C beta-1 through protein interaction (inferred from homologues in Bos taurus). The activation by Gq alpha is insensitive to pertussis toxin whilst activation of PLC beta by the G beta-gamma complex is sensitive to pertussis toxin.
REACT_18428 (Reactome) Intrapancreatic parasympathetic (vagal) nerve endings release acetylcholine during preabsorptive and absorptive phases of feeding. The acetylcholine binds Muscarinic Acetylcholine Receptor M3 on pancreatic islet beta cells (inferred from experiments with knockout mice).
REACT_18430 (Reactome) ATP-sensitive Potassium channels open and allow an inward rectifying current of potassium ions to flow, reestablishing the resting potential of the cell.
REACT_18433 (Reactome) The binding of GTP by G(s) alpha causes the heterotrimeric G-protein complex to reorientate, exposing previously bound faces of the G(s) alpha:GTP complex and the G-beta: G-gamma complex. Unlike the case with Gi/o heterotrimers, Gs heterotrimers are not observed to significantly dissociate in living cells.
REACT_1891 (Reactome) At the end of this reaction, 1 molecule of 'pyruvate kinase, liver and RBC' is present.

This reaction takes place in the 'nucleus'.

REACT_19346 (Reactome) FFAR1 (GPR40) is a G-protein coupled receptor. Based on studies with inhibitors of G proteins such as pertussis toxin FFAR1 is believed to signal through Gq/11. Binding of free fatty acids by FFAR1 activates the heterotrimeric Gq complex, which then activates Phospholipase C. From experiments in knockout mice it is estimated that signaling through FFAR1 is responsible for about 50% of the augmentation of insulin secretion produced by free fatty acids. The rest of the augmentation is due to metabolism of the free fatty acids within the pancreatic beta cell.
REACT_19366 (Reactome) Free fatty acid receptor 1 (FFAR1), also known as GPR40, is a G-protein coupled receptor located in the plasma membrane of pancreatic beta cells. FFAR1/GPR40 binds medium and long chain free fatty acids (free fatty acids having more than 12 carbon groups).
REACT_2128 (Reactome) Activated PKA (protein kinase A) phosphorylates serine 36 of the bifunctional 6-Phosphofructo-2-kinase /Fructose-2,6-bisphosphatase (PFKFB1) enzyme. This phosphorylation inhibits the enzyme's phosphofructokinase (PFK-2) activity while activating its phosphatase activity. As a result, cytosolic levels of Fructose-2,6-bisphosphate (F-2,6-P2) are reduced. F-2,6-P2 in turn is a key positive regulator of the committed step of glycolysis, so the net effect of this phosphorylation event is a reduced rate of glycolysis.
REACT_21415 (Reactome) Human pancreatic beta cells express glucose transporters 1 and (GLUT1, GLUT2), which are responsible for uptake of glucose from the extracellular medium into the cytosol. (Rodent pancreatic beta cells express only Glut2.)
REACT_2177 (Reactome) Xylulose-5-phosphate binds to Protein phosphatase 2A (PP2A), activating it. This regulatory step may be the crucial physiological link explaining the coordinately increased rates of glycolysis and lipogenesis generally observed in individuals consuming high-carbohydrate diets.
REACT_22110 (Reactome) The G(s)alpha G-beta G-gamma complex bound to glucagon, in the plasma membrane, releases a molecule of bound GDP, binds a molecule of GTP, and dissociates to yield a G(s)alpha:GTP complex and a G-beta:G-gamma dimer.
REACT_2219 (Reactome) G(s)-alpha:GTP binds to inactive adenylate cyclase, causing a conformational transition in adenylate cyclase exposing the catalytic site and activating it.
REACT_229 (Reactome) At the end of this reaction, 1 molecule of 'Fatty acid synthase ' is present.

This reaction takes place in the 'nucleus'.

REACT_304 (Reactome) In its active (unphosphorylated) form, ChREBP (Carbohydrate Response Element Binding Protein) binds so-called ChRE (Carbohydrate Response Element) DNA sequence motifs found upstream of several genes involved in glucose utilization and lipid synthesis, activating transcription of these genes. Phosphorylation of ChREBP at threonine residue 666 by PKA (protein kinase A) blocks this binding activity, and thus has the effect of down-regulating expression of the target genes. ChREBP phosphorylation can be reversed by the action of protein phosphatase 2A (PP2A).
REACT_349 (Reactome) In the nucleus, activated AMPK phosphorylates serine residue 568 of ChREBP (Carbohydrate Response Element Binding Protein). Phosphorylated ChREBP does not bind to ChRE chromosomal DNA sequence elements and thus loses its ability to promote transcription of genes involved in glycolysis and lipogenesis.
REACT_355 (Reactome) At the end of this reaction, 1 molecule of 'Acetyl-CoA carboxylase 2 ' is present.

This reaction takes place in the 'nucleus'.

REACT_382 (Reactome) At the beginning of this reaction, 1 molecule of 'pChREBP (Thr 666)' is present. At the end of this reaction, 1 molecule of 'Orthophosphate', and 1 molecule of 'ChREBP protein' are present.

This reaction takes place in the 'nucleus' and is mediated by the 'phosphatidate phosphatase activity' of 'PP2A-ABdeltaC complex'.

REACT_483 (Reactome) Phosphorylation of ChREBP (Carbohydrate Response Element Binding Protein) at serine 196 by PKA inhibits its nuclear translocation. This reaction has been studied in detail using mouse proteins (Kawaguchi et al. 2001); the human version of the reaction is inferred from these studies.
REACT_548 (Reactome) ChREBP (Carbohydrate Response Element Binding Protein) doubly phosphorylated at threonine 666 and serine 196 is inactive and is localized to the cytosol. Removal of the phosphate residue at serine 196 allows ChREBP to translocate between the cytosol and the nucleoplasm.
REACT_627 (Reactome) At the beginning of this reaction, 1 molecule of 'AMPK heterotrimer (inactive)', and 1 molecule of 'AMP' are present. At the end of this reaction, 1 molecule of 'AMPK heterotrimer:AMP' is present.

This reaction takes place in the 'nucleus'.

REACT_787 (Reactome) At the end of this reaction, 1 molecule of '1-acyl-sn-glycerol-3-phosphate acyltransferase alpha ' is present.

This reaction takes place in the 'nucleus'.

REACT_814 (Reactome) At the beginning of this reaction, 1 molecule of 'pChREBP(Ser 568)' is present. At the end of this reaction, 1 molecule of 'Orthophosphate', and 1 molecule of 'ChREBP protein' are present.

This reaction takes place in the 'nucleus' and is mediated by the 'phosphatidate phosphatase activity' of 'PP2A-ABdeltaC complex'.

REACT_9011 (Reactome) A family of antiport, ATP-ADP translocases, preferentially export ATP from the matrix while importing ADP from the cytosol, thereby maintaining a high ADP:ATP ratio in the matrix. When there are increased energy demands on the body, such as under heavy exercise, cytosolic ADP rises and is exchanged with mitochondrial matrix ATP via the transmembrane ADP:ATP translocase. Increased ADP causes the proton-motive force to be discharged and protons enter via ATPase, thereby regenerating the ATP pool.
There are 3 isoforms of translocases in humans; isoform 1 is the heart/skeletal muscle form, isoform 2 is the fibroblast form and isoform 3 is the liver form. All isoforms exist as homodimers. The translocase can adopt 2 different conformations, called the CATR (carboxyatractyloside) and BA (bongkrekic acid) conformations. Amongst the endogenous nucleotides, only ADP and ATP can trigger the rapid conversion between the CATR and BA conformations.
The reaction can be summed as below:
ADPout + ATPin <-> ADPin + ATPout

Rap1-GDPREACT_18379 (Reactome)
Rap1-GTPArrowREACT_18379 (Reactome)
SNAP25REACT_15326 (Reactome)
SNARE ComplexArrowREACT_15326 (Reactome)
STK11REACT_1325 (Reactome)
STX1A STXBP1REACT_15326 (Reactome)
STXBP1ArrowREACT_15326 (Reactome)
SYT5REACT_15326 (Reactome)
Sedoheptulose 7-phosphateArrowREACT_1272 (Reactome)
Sedoheptulose 7-phosphateREACT_1450 (Reactome)
TALDO1REACT_1272 (Reactome)
VAMP2REACT_15326 (Reactome)
Voltage-gated Calcium Channels REACT_16913 (Reactome)
Voltage-gated Calcium Channels Type Cav1 TBarREACT_15326 (Reactome)
XY5PArrowREACT_1450 (Reactome)
XY5PArrowREACT_1730 (Reactome)
XY5PArrowREACT_2177 (Reactome)
cAMP

PKA AKAP79

IQGAP1 Complex		ArrowREACT_18397 (Reactome)
cAMP PKA regulatory subunitArrowREACT_1532 (Reactome)
mature GLP-1REACT_18260 (Reactome)
p-4S-MARCKSArrowREACT_18263 (Reactome)
p-S196,T666-MLXIPLArrowREACT_483 (Reactome)
p-S568-MLXIPLArrowREACT_349 (Reactome)
p-T666-MLXIPLArrowREACT_1416 (Reactome)
p-T666-MLXIPLArrowREACT_304 (Reactome)
p-T666-MLXIPLREACT_483 (Reactome)
phosphoPFKFB1 dimerArrowREACT_2128 (Reactome)
phosphoPFKFB1 dimerREACT_1347 (Reactome)
transketolase dimerREACT_1450 (Reactome)
transketolase dimerREACT_1730 (Reactome)
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