Integration of energy metabolism (Homo sapiens)

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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.). View original pathway at:Reactome.

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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
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
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
Veech RL.; ''A humble hexose monophosphate pathway metabolite regulates short- and long-term control of lipogenesis.''; PubMed Europe PMC Scholia
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
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
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
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
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
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
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
Gromada J, Brock B, Schmitz O, Rorsman P.; ''Glucagon-like peptide-1: regulation of insulin secretion and therapeutic potential.''; PubMed Europe PMC Scholia
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
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
Tsuboi T, Rutter GA.; ''Insulin secretion by 'kiss-and-run' exocytosis in clonal pancreatic islet beta-cells.''; PubMed Europe PMC Scholia
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
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
Henquin JC, Ishiyama N, Nenquin M, Ravier MA, Jonas JC.; ''Signals and pools underlying biphasic insulin secretion.''; PubMed Europe PMC Scholia
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
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
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
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
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
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
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
Cheng H, Straub SG, Sharp GW.; ''Protein acylation in the inhibition of insulin secretion by norepinephrine, somatostatin, galanin, and PGE2.''; PubMed Europe PMC Scholia
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
Barg S, Rorsman P.; ''Insulin secretion: a high-affinity Ca2+ sensor after all?''; PubMed Europe PMC Scholia
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
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
Yang SN, Berggren PO.; ''The role of voltage-gated calcium channels in pancreatic beta-cell physiology and pathophysiology.''; PubMed Europe PMC Scholia
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
Jiang G, Zhang BB.; ''Glucagon and regulation of glucose metabolism.''; PubMed Europe PMC Scholia
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
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
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
Doyle ME, Egan JM.; ''Mechanisms of action of glucagon-like peptide 1 in the pancreas.''; PubMed Europe PMC Scholia

History

View all...

Revision	Action	Time	User	Comment
114967	view	16:49, 25 January 2021	ReactomeTeam	Reactome version 75
113411	view	11:48, 2 November 2020	ReactomeTeam	Reactome version 74
112613	view	15:59, 9 October 2020	ReactomeTeam	Reactome version 73
101529	view	11:39, 1 November 2018	ReactomeTeam	reactome version 66
101064	view	21:21, 31 October 2018	ReactomeTeam	reactome version 65
100595	view	19:56, 31 October 2018	ReactomeTeam	reactome version 64
100144	view	16:41, 31 October 2018	ReactomeTeam	reactome version 63
99694	view	15:10, 31 October 2018	ReactomeTeam	reactome version 62 (2nd attempt)
99282	view	12:46, 31 October 2018	ReactomeTeam	reactome version 62
93853	view	13:41, 16 August 2017	ReactomeTeam	reactome version 61
93414	view	11:23, 9 August 2017	ReactomeTeam	reactome version 61
86502	view	09:19, 11 July 2016	ReactomeTeam	reactome version 56
83173	view	10:17, 18 November 2015	ReactomeTeam	Version54
81543	view	13:05, 21 August 2015	ReactomeTeam	Version53
77011	view	08:30, 17 July 2014	ReactomeTeam	Fixed remaining interactions
76716	view	12:08, 16 July 2014	ReactomeTeam	Fixed remaining interactions
76042	view	10:10, 11 June 2014	ReactomeTeam	Re-fixing comment source
75751	view	11:24, 10 June 2014	ReactomeTeam	Reactome 48 Update
75101	view	14:05, 8 May 2014	Anwesha	Fixing comment source for displaying WikiPathways description
74748	view	08:49, 30 April 2014	ReactomeTeam	Reactome46
72912	view	15:20, 14 December 2013	Egonw	Fixed the Uniprot-TrEMBL data sources.
69896	view	19:21, 11 July 2013	MaintBot	updated to 2013 schema
44859	view	09:54, 6 October 2011	MartijnVanIersel	Ontology Term : 'energy metabolic pathway' added !
42162	view	23:28, 4 March 2011	MaintBot	Modified categories
42052	view	21:53, 4 March 2011	MaintBot	Automatic update
39857	view	05:53, 21 January 2011	MaintBot	New pathway

External references

DataNodes

View all...

Name	Type	Database reference	Comment
2xHC-INS(25-54)	Protein	P01308 (Uniprot-TrEMBL)
4xHC-INS(90-110)	Protein	P01308 (Uniprot-TrEMBL)
6xInsulin:2xZn2+:Ca2+ (docked granule)	Complex	R-HSA-386977 (Reactome)
ABCC8	Protein	Q09428 (Uniprot-TrEMBL)
ACACB	Protein	O00763 (Uniprot-TrEMBL)
ACC	Complex	R-HSA-200563 (Reactome)
ACLY	Protein	P53396 (Uniprot-TrEMBL)
ADCY1	Protein	Q08828 (Uniprot-TrEMBL)
ADCY2	Protein	Q08462 (Uniprot-TrEMBL)
ADCY3	Protein	O60266 (Uniprot-TrEMBL)
ADCY4	Protein	Q8NFM4 (Uniprot-TrEMBL)
ADCY5	Protein	O95622 (Uniprot-TrEMBL)
ADCY5,6,8:G-alpha(s):GTP	Complex	R-HSA-422306 (Reactome)
ADCY6	Protein	O43306 (Uniprot-TrEMBL)
ADCY7	Protein	P51828 (Uniprot-TrEMBL)
ADCY8	Protein	P40145 (Uniprot-TrEMBL)
ADCY9	Protein	O60503 (Uniprot-TrEMBL)
ADP	Metabolite	CHEBI:16761 (ChEBI)
ADP	Metabolite	CHEBI:16761 (ChEBI)
ADR	Metabolite	CHEBI:28918 (ChEBI)
ADR, NAd	Complex	R-HSA-R-ALL-400049 (Reactome)
ADRA2A	Protein	P08913 (Uniprot-TrEMBL)
ADRA2A,C:ADR,NAd	Complex	R-HSA-400090 (Reactome)
ADRA2A,C	Complex	R-HSA-400086 (Reactome)
ADRA2C	Protein	P18825 (Uniprot-TrEMBL)
AGPAT1	Protein	Q99943 (Uniprot-TrEMBL)
AHCYL1	Protein	O43865 (Uniprot-TrEMBL)
AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramer	Complex	R-HSA-5226920 (Reactome)
AKAP5	Protein	P24588 (Uniprot-TrEMBL)
AMP	Metabolite	CHEBI:16027 (ChEBI)
AMP	Metabolite	CHEBI:16027 (ChEBI)
AMPK heterotrimer:AMP	Complex	R-HSA-163747 (Reactome)
AMPK heterotrimer (inactive)	Complex	R-HSA-163679 (Reactome)
ARL2	Protein	P36404 (Uniprot-TrEMBL)
ARL2:GTP:ARL2BP:SLC25A4	Complex	R-HSA-5250205 (Reactome)
ARL2:GTP:ARL2BP	Complex	R-HSA-5250201 (Reactome)
ARL2:GTP:ARL2BP	Complex	R-HSA-5250221 (Reactome)
ARL2:GTP	Complex	R-HSA-5250197 (Reactome)
ARL2BP	Protein	Q9Y2Y0 (Uniprot-TrEMBL)
ARL2BP	Protein	Q9Y2Y0 (Uniprot-TrEMBL)
ATP	Metabolite	CHEBI:15422 (ChEBI)
ATP	Metabolite	CHEBI:15422 (ChEBI)
AcCho	Metabolite	CHEBI:15355 (ChEBI)
AcCho	Metabolite	CHEBI:15355 (ChEBI)
Activated AMPK heterotrimer	Complex	R-HSA-163736 (Reactome)
Adenylate Cyclase V or VI	Complex	R-HSA-446432 (Reactome)
Adenylate cyclase (Mg2+ cofactor)	Complex	R-HSA-170665 (Reactome)
Adenylate cyclase type V or VI: G-protein beta gamma Complex	Complex	R-HSA-400038 (Reactome)
Adenylyl cyclase (pancreatic beta cell)	Complex	R-HSA-446658 (Reactome)
ArgN-GCG(98-127)	Protein	P01275 (Uniprot-TrEMBL)	The amide group at the C-terminus is not necessary for biological activity.
Btn-ACACA	Protein	Q13085 (Uniprot-TrEMBL)
CACNA1A	Protein	O00555 (Uniprot-TrEMBL)
CACNA1C	Protein	Q13936 (Uniprot-TrEMBL)
CACNA1D	Protein	Q01668 (Uniprot-TrEMBL)
CACNA1E	Protein	Q15878 (Uniprot-TrEMBL)
CACNA2D2(19-1150)	Protein	Q9NY47 (Uniprot-TrEMBL)
CACNB2	Protein	Q08289 (Uniprot-TrEMBL)
CACNB3	Protein	P54284 (Uniprot-TrEMBL)
CHRM3	Protein	P20309 (Uniprot-TrEMBL)
CHRM3	Protein	P20309 (Uniprot-TrEMBL)
Ca-channel (closed)	Complex	R-HSA-111877 (Reactome)
Ca-channel (open)	Complex	R-HSA-111873 (Reactome)
Ca2+	Metabolite	CHEBI:29108 (ChEBI)
Ca2+	Metabolite	CHEBI:29108 (ChEBI)
ChREBP:MLX	Complex	R-HSA-163700 (Reactome)
Core SNARE Complex	Complex	R-HSA-387383 (Reactome)
DAG	Metabolite	CHEBI:17815 (ChEBI)
DAG		CHEBI:17815 (ChEBI)
DDCX	Metabolite	CHEBI:30805 (ChEBI)
E4P	Metabolite	CHEBI:16897 (ChEBI)
FASN	Protein	P49327 (Uniprot-TrEMBL)
FFAR1	Protein	O14842 (Uniprot-TrEMBL)
FFAR1:fatty acid	Complex	R-HSA-400420 (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	Protein	O14842 (Uniprot-TrEMBL)
Fatty acids		R-NUL-163730 (Reactome)
Fru(6)P	Metabolite	CHEBI:15946 (ChEBI)
G-alpha(i,o):GDP:G beta:G gamma	Complex	R-HSA-400088 (Reactome)
G-alpha(i,o):GTP:G-beta:G-gamma	Complex	R-HSA-400031 (Reactome)
G-alpha(i,o):GTP	Complex	R-HSA-400076 (Reactome)
G-alpha(q) 11,14,15,Q:GTP	Complex	R-HSA-400008 (Reactome)
G-alpha(q)11,14,15,Q:G-beta:G-gamma	Complex	R-HSA-399987 (Reactome)
G-alpha(q)11,14,15,Q:GDP:G-beta:G-gamma	Complex	R-HSA-399992 (Reactome)
G-alpha(s):GTP:G-beta:G-gamma	Complex	R-HSA-422322 (Reactome)
G-beta:G-gamma (candidates)	Complex	R-HSA-400034 (Reactome)
G-beta:G-gamma dimer	Complex	R-HSA-164386 (Reactome)
G-beta:G-gamma	Complex	R-HSA-399993 (Reactome)
G-protein alpha (s):GTP	Complex	R-HSA-164358 (Reactome)
G-protein with G(s) alpha:GDP	Complex	R-HSA-164384 (Reactome)
GA3P	Metabolite	CHEBI:29052 (ChEBI)
GCGR	Protein	P47871 (Uniprot-TrEMBL)
GCGR	Protein	P47871 (Uniprot-TrEMBL)
GDP	Metabolite	CHEBI:17552 (ChEBI)
GDP	Metabolite	CHEBI:17552 (ChEBI)
GLP-1 (7-37)	Protein	P01275 (Uniprot-TrEMBL)
GLP-1:GLP-1R:Heterotrimeric G(s):GDP	Complex	R-HSA-422310 (Reactome)
GLP-1:GLP-1R:Heterotrimeric G(s):GTP	Complex	R-HSA-422311 (Reactome)
GLP-1R:Heterotrimeric G(s):GDP	Complex	R-HSA-422314 (Reactome)
GLP1R	Protein	P43220 (Uniprot-TrEMBL)
GLUT1,2	Complex	R-HSA-500048 (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.
GNA11	Protein	P29992 (Uniprot-TrEMBL)
GNA14	Protein	O95837 (Uniprot-TrEMBL)
GNA15	Protein	P30679 (Uniprot-TrEMBL)
GNAI1	Protein	P63096 (Uniprot-TrEMBL)
GNAI2	Protein	P04899 (Uniprot-TrEMBL)
GNAQ	Protein	P50148 (Uniprot-TrEMBL)
GNAS	Protein	P63092 (Uniprot-TrEMBL)
GNB1	Protein	P62873 (Uniprot-TrEMBL)
GNB2	Protein	P62879 (Uniprot-TrEMBL)
GNB3	Protein	P16520 (Uniprot-TrEMBL)
GNB4	Protein	Q9HAV0 (Uniprot-TrEMBL)
GNB5	Protein	O14775 (Uniprot-TrEMBL)
GNG10	Protein	P50151 (Uniprot-TrEMBL)
GNG11	Protein	P61952 (Uniprot-TrEMBL)
GNG12	Protein	Q9UBI6 (Uniprot-TrEMBL)
GNG13	Protein	Q9P2W3 (Uniprot-TrEMBL)
GNG2	Protein	P59768 (Uniprot-TrEMBL)
GNG3	Protein	P63215 (Uniprot-TrEMBL)
GNG4	Protein	P50150 (Uniprot-TrEMBL)
GNG5	Protein	P63218 (Uniprot-TrEMBL)
GNG7	Protein	O60262 (Uniprot-TrEMBL)
GNG8	Protein	Q9UK08 (Uniprot-TrEMBL)
GNGT1	Protein	P63211 (Uniprot-TrEMBL)
GNGT2	Protein	O14610 (Uniprot-TrEMBL)
GTP	Metabolite	CHEBI:15996 (ChEBI)
GTP	Metabolite	CHEBI:15996 (ChEBI)
Glc	Metabolite	CHEBI:17925 (ChEBI)
Glucagon	Protein	P01275 (Uniprot-TrEMBL)
Glucagon:GCGR	Complex	R-HSA-163627 (Reactome)
Glucagon	Protein	P01275 (Uniprot-TrEMBL)
Gs-activated adenylate cyclase	Complex	R-HSA-163622 (Reactome)
Guanine nucleotide-binding protein beta subunit		R-HSA-114545 (Reactome)
Guanine nucleotide-binding protein gamma subunit		R-HSA-114546 (Reactome)
H2O	Metabolite	CHEBI:15377 (ChEBI)
I(1,4,5)P3	Metabolite	CHEBI:16595 (ChEBI)
I(1,4,5)P3	Metabolite	CHEBI:16595 (ChEBI)
INS(57-87)	Protein	P01308 (Uniprot-TrEMBL)
IP3 receptor homotetramer	Complex	R-HSA-169686 (Reactome)
IQGAP1	Protein	P46940 (Uniprot-TrEMBL)
ITPR1	Protein	Q14643 (Uniprot-TrEMBL)
ITPR2	Protein	Q14571 (Uniprot-TrEMBL)
ITPR3	Protein	Q14573 (Uniprot-TrEMBL)
ITPR:I(1,4,5)P3 tetramer	Complex	R-HSA-169696 (Reactome)
Inactive PP2A-ABdeltaC complex	Complex	R-HSA-165992 (Reactome)
Insulin	Complex	R-HSA-74674 (Reactome)
KCNB1	Protein	Q14721 (Uniprot-TrEMBL)
KCNC2	Protein	Q96PR1 (Uniprot-TrEMBL)
KCNG2	Protein	Q9UJ96 (Uniprot-TrEMBL)
KCNJ11 tetramer:ABCC8:Mg2+:ADP tetramer	Complex	R-HSA-265734 (Reactome)
KCNJ11	Protein	Q14654 (Uniprot-TrEMBL)
KCNJ11:ATP tetramer:ABCC8 tetramer	Complex	R-HSA-265746 (Reactome)
KCNS3	Protein	Q9BQ31 (Uniprot-TrEMBL)
Ligands of FFAR1 (GPR40)	Complex	R-HSA-R-ALL-400427 (Reactome)
MARCKS	Protein	P29966 (Uniprot-TrEMBL)
MLX	Protein	Q9UH92 (Uniprot-TrEMBL)
MLXIPL	Protein	Q9NP71 (Uniprot-TrEMBL)
MLXIPL	Protein	Q9NP71 (Uniprot-TrEMBL)
MLX	Protein	Q9UH92 (Uniprot-TrEMBL)
Mg2+	Metabolite	CHEBI:18420 (ChEBI)
Mg2+:ADP	Complex	R-HSA-R-ALL-6790050 (Reactome)
Muscarinic Acetylcholine Receptor M3:Acetylcholine Complex	Complex	R-HSA-400013 (Reactome)
NAD+	Metabolite	CHEBI:15846 (ChEBI)
NAd	Metabolite	CHEBI:18357 (ChEBI)
OLEA	Metabolite	CHEBI:16196 (ChEBI)
PALM	Metabolite	CHEBI:15756 (ChEBI)
PFKFB1	Protein	P16118 (Uniprot-TrEMBL)
PFKFB1 dimer	Complex	R-HSA-71786 (Reactome)
PI(4,5)P2	Metabolite	CHEBI:18348 (ChEBI)
PKA catalytic subunit	Complex	R-HSA-111920 (Reactome)
PKA tetramer	Complex	R-HSA-111922 (Reactome)
PKA:AKAP79:IQGAP1 Complex	Complex	R-HSA-381635 (Reactome)
PKLR-1	Protein	P30613-1 (Uniprot-TrEMBL)
PLC beta1,2,3:G-alpha(q):GTP	Complex	R-HSA-400011 (Reactome)
PLC beta1,2,3	Complex	R-HSA-400005 (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).
PLCB1	Protein	Q9NQ66 (Uniprot-TrEMBL)
PLCB2	Protein	Q00722 (Uniprot-TrEMBL)
PLCB3	Protein	Q01970 (Uniprot-TrEMBL)
PP2A-ABdeltaC complex	Complex	R-HSA-165961 (Reactome)
PP2A-ABdeltaC complex	Complex	R-HSA-165970 (Reactome)
PPP2CA	Protein	P67775 (Uniprot-TrEMBL)
PPP2CB	Protein	P62714 (Uniprot-TrEMBL)
PPP2R1A	Protein	P30153 (Uniprot-TrEMBL)
PPP2R1B	Protein	P30154 (Uniprot-TrEMBL)
PPP2R5D	Protein	Q14738 (Uniprot-TrEMBL)
PPi	Metabolite	CHEBI:29888 (ChEBI)
PRKAA2	Protein	P54646 (Uniprot-TrEMBL)
PRKAB2	Protein	O43741 (Uniprot-TrEMBL)
PRKACA	Protein	P17612 (Uniprot-TrEMBL)
PRKACB	Protein	P22694 (Uniprot-TrEMBL)
PRKACG	Protein	P22612 (Uniprot-TrEMBL)
PRKAG2	Protein	Q9UGJ0 (Uniprot-TrEMBL)
PRKAR1A	Protein	P10644 (Uniprot-TrEMBL)
PRKAR1B	Protein	P31321 (Uniprot-TrEMBL)
PRKAR2A	Protein	P13861 (Uniprot-TrEMBL)
PRKAR2B	Protein	P31323 (Uniprot-TrEMBL)
PRKCA	Protein	P17252 (Uniprot-TrEMBL)
PRKCA	Protein	P17252 (Uniprot-TrEMBL)
Pentadecanoic acid	Metabolite	CHEBI:42504 (ChEBI)
Pi	Metabolite	CHEBI:18367 (ChEBI)
Potassium voltage-gated channels (beta cell, closed)	Complex	R-HSA-381655 (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 (beta cell, open)	Complex	R-HSA-381640 (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 Channel, closed (pancreatic beta cell)		R-HSA-446513 (Reactome)
Potassium Channel, open (pancreatic beta cell)		R-HSA-446505 (Reactome)
Protein Kinase A, catalytic subunits	Complex	R-HSA-111917 (Reactome)
Protein Kinase C, alpha type: DAG	Complex	R-HSA-422275 (Reactome)
R5P	Metabolite	CHEBI:78679 (ChEBI)
RAP1A	Protein	P62834 (Uniprot-TrEMBL)
RAP1A:GDP	Complex	R-HSA-5252143 (Reactome)
RAP1A:GTP	Complex	R-HSA-5252145 (Reactome)
RAPGEF3	Protein	O95398 (Uniprot-TrEMBL)
RAPGEF3:cAMP complex	Complex	R-HSA-381702 (Reactome)
RAPGEF3	Protein	O95398 (Uniprot-TrEMBL)
RAPGEF4	Protein	Q8WZA2 (Uniprot-TrEMBL)
RAPGEF4:cAMP Complex	Complex	R-HSA-381680 (Reactome)
RAPGEF4	Protein	Q8WZA2 (Uniprot-TrEMBL)
RGZ	Metabolite	CHEBI:50122 (ChEBI)
SH7P	Metabolite	CHEBI:15721 (ChEBI)
SLC25A4	Protein	P12235 (Uniprot-TrEMBL)
SLC25A4	Protein	P12235 (Uniprot-TrEMBL)
SLC25A5	Protein	P05141 (Uniprot-TrEMBL)
SLC25A5,6 dimers	Complex	R-HSA-187453 (Reactome)
SLC25A6	Protein	P12236 (Uniprot-TrEMBL)
SLC2A1	Protein	P11166 (Uniprot-TrEMBL)
SLC2A2	Protein	P11168 (Uniprot-TrEMBL)
SNAP25	Protein	P60880 (Uniprot-TrEMBL)
SNAP25	Protein	P60880 (Uniprot-TrEMBL)
SNARE Complex	Complex	R-HSA-265202 (Reactome)
STK11	Protein	Q15831 (Uniprot-TrEMBL)
STX1A	Protein	Q16623 (Uniprot-TrEMBL)
STX1A:STXBP1	Complex	R-HSA-265191 (Reactome)
STXBP1	Protein	P61764 (Uniprot-TrEMBL)
STXBP1	Protein	P61764 (Uniprot-TrEMBL)
SYT5	Protein	O00445 (Uniprot-TrEMBL)
SYT5	Protein	O00445 (Uniprot-TrEMBL)
TALDO1	Protein	P37837 (Uniprot-TrEMBL)
TALDO1 dimer	Complex	R-HSA-5659970 (Reactome)
TALDO1	Protein	P37837 (Uniprot-TrEMBL)
TKT	Protein	P29401 (Uniprot-TrEMBL)
ThDP	Metabolite	CHEBI:9532 (ChEBI)
VAMP2	Protein	P63027 (Uniprot-TrEMBL)
VAMP2	Protein	P63027 (Uniprot-TrEMBL)
Voltage-gated Calcium Channels (pancreatic beta cell)	Complex	R-HSA-265569 (Reactome)
Voltage-gated Calcium Channels Type Cav1 (closed)	Complex	R-HSA-400095 (Reactome)
Voltage-gated Calcium Channels Type Cav1 (open)	Complex	R-HSA-400055 (Reactome)
XY5P	Metabolite	CHEBI:57737 (ChEBI)
Zn2+	Metabolite	CHEBI:29105 (ChEBI)
Zn2+	Metabolite	CHEBI:29105 (ChEBI)
cAMP	Metabolite	CHEBI:17489 (ChEBI)
cAMP:PKA regulatory subunit	Complex	R-HSA-111923 (Reactome)
cAMP:PKA:AKAP79:IQGAP1 Complex	Complex	R-HSA-381615 (Reactome)
cAMP	Metabolite	CHEBI:17489 (ChEBI)
mature GLP-1	Complex	R-HSA-381662 (Reactome)
p-4S-MARCKS	Protein	P29966 (Uniprot-TrEMBL)
p-S196,T666-MLXIPL	Protein	Q9NP71 (Uniprot-TrEMBL)
p-S33-PFKFB1	Protein	P16118 (Uniprot-TrEMBL)
p-S568-MLXIPL	Protein	Q9NP71 (Uniprot-TrEMBL)
p-T172-PRKAA2	Protein	P54646 (Uniprot-TrEMBL)
p-T666-MLXIPL	Protein	Q9NP71 (Uniprot-TrEMBL)
phosphoPFKFB1 dimer	Complex	R-HSA-163745 (Reactome)
transketolase dimer	Complex	R-HSA-71322 (Reactome)

Annotated Interactions

View all...

Source	Target	Type	Database reference	Comment
6xInsulin:2xZn2+:Ca2+ (docked granule)			R-HSA-265166 (Reactome)
	ACC	Arrow	R-HSA-163743 (Reactome)
	ACLY	Arrow	R-HSA-163770 (Reactome)
	ADCY5,6,8:G-alpha(s):GTP	Arrow	R-HSA-381704 (Reactome)
ADCY5,6,8:G-alpha(s):GTP		mim-catalysis	R-HSA-381607 (Reactome)
	ADP	Arrow	R-HSA-163215 (Reactome)
	ADP	Arrow	R-HSA-163672 (Reactome)
	ADP	Arrow	R-HSA-163676 (Reactome)
	ADP	Arrow	R-HSA-163691 (Reactome)
	ADP	Arrow	R-HSA-163773 (Reactome)
	ADP	Arrow	R-HSA-164151 (Reactome)
	ADP	Arrow	R-HSA-399978 (Reactome)
	ADP	Arrow	R-HSA-5672027 (Reactome)
ADP			R-HSA-163215 (Reactome)
ADP			R-HSA-5672027 (Reactome)
ADR, NAd			R-HSA-400071 (Reactome)
	ADRA2A,C:ADR,NAd	Arrow	R-HSA-400071 (Reactome)
ADRA2A,C:ADR,NAd		Arrow	R-HSA-400092 (Reactome)
ADRA2A,C			R-HSA-400071 (Reactome)
	AGPAT1	Arrow	R-HSA-163748 (Reactome)
AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramer		TBar	R-HSA-169683 (Reactome)
	AMPK heterotrimer:AMP	Arrow	R-HSA-163664 (Reactome)
AMPK heterotrimer:AMP			R-HSA-164151 (Reactome)
AMPK heterotrimer (inactive)			R-HSA-163664 (Reactome)
AMP			R-HSA-163664 (Reactome)
AMP		TBar	R-HSA-163691 (Reactome)
	ARL2:GTP:ARL2BP:SLC25A4	Arrow	R-HSA-5250209 (Reactome)
ARL2:GTP:ARL2BP:SLC25A4		mim-catalysis	R-HSA-5672027 (Reactome)
	ARL2:GTP:ARL2BP	Arrow	R-HSA-5250210 (Reactome)
	ARL2:GTP:ARL2BP	Arrow	R-HSA-5250217 (Reactome)
ARL2:GTP:ARL2BP			R-HSA-5250209 (Reactome)
ARL2:GTP:ARL2BP			R-HSA-5250210 (Reactome)
ARL2:GTP			R-HSA-5250217 (Reactome)
ARL2BP			R-HSA-5250217 (Reactome)
	ATP	Arrow	R-HSA-163215 (Reactome)
	ATP	Arrow	R-HSA-5672027 (Reactome)
ATP			R-HSA-163215 (Reactome)
ATP			R-HSA-163672 (Reactome)
ATP			R-HSA-163676 (Reactome)
ATP			R-HSA-163691 (Reactome)
ATP			R-HSA-163773 (Reactome)
ATP			R-HSA-164151 (Reactome)
ATP			R-HSA-164377 (Reactome)
ATP			R-HSA-265682 (Reactome)
ATP			R-HSA-381607 (Reactome)
ATP			R-HSA-399978 (Reactome)
ATP			R-HSA-5672027 (Reactome)
AcCho			R-HSA-400012 (Reactome)
	Activated AMPK heterotrimer	Arrow	R-HSA-164151 (Reactome)
Activated AMPK heterotrimer		mim-catalysis	R-HSA-163691 (Reactome)
Adenylate Cyclase V or VI			R-HSA-400097 (Reactome)
Adenylate cyclase (Mg2+ cofactor)			R-HSA-163617 (Reactome)
	Adenylate cyclase type V or VI: G-protein beta gamma Complex	Arrow	R-HSA-400097 (Reactome)
Adenylyl cyclase (pancreatic beta cell)			R-HSA-381704 (Reactome)
		Arrow	R-HSA-265682 (Reactome)
CHRM3			R-HSA-400012 (Reactome)
Ca-channel (closed)			R-HSA-381644 (Reactome)
	Ca-channel (open)	Arrow	R-HSA-381644 (Reactome)
	Ca2+	Arrow	R-HSA-169683 (Reactome)
	Ca2+	Arrow	R-HSA-265166 (Reactome)
	Ca2+	Arrow	R-HSA-265645 (Reactome)
Ca2+			R-HSA-169683 (Reactome)
Ca2+			R-HSA-265166 (Reactome)
Ca2+			R-HSA-265645 (Reactome)
	ChREBP:MLX	Arrow	R-HSA-163666 (Reactome)
ChREBP:MLX		Arrow	R-HSA-163669 (Reactome)
ChREBP:MLX		Arrow	R-HSA-163733 (Reactome)
ChREBP:MLX		Arrow	R-HSA-163743 (Reactome)
ChREBP:MLX		Arrow	R-HSA-163748 (Reactome)
ChREBP:MLX		Arrow	R-HSA-163770 (Reactome)
Core SNARE Complex		mim-catalysis	R-HSA-265166 (Reactome)
	DAG	Arrow	R-HSA-399998 (Reactome)
DAG			R-HSA-400015 (Reactome)
	E4P	Arrow	R-HSA-163751 (Reactome)
E4P			R-HSA-163764 (Reactome)
	FASN	Arrow	R-HSA-163733 (Reactome)
	FFAR1:fatty acid	Arrow	R-HSA-400434 (Reactome)
FFAR1:fatty acid		mim-catalysis	R-HSA-416530 (Reactome)
FFAR1			R-HSA-400434 (Reactome)
Fatty acids		Arrow	R-HSA-163691 (Reactome)
Fru(6)P			R-HSA-163751 (Reactome)
Fru(6)P			R-HSA-163764 (Reactome)
G-alpha(i,o):GDP:G beta:G gamma			R-HSA-400092 (Reactome)
	G-alpha(i,o):GTP:G-beta:G-gamma	Arrow	R-HSA-400092 (Reactome)
G-alpha(i,o):GTP:G-beta:G-gamma			R-HSA-400037 (Reactome)
	G-alpha(i,o):GTP	Arrow	R-HSA-400037 (Reactome)
G-alpha(i,o):GTP		Arrow	R-HSA-400063 (Reactome)
G-alpha(i,o):GTP		TBar	R-HSA-265166 (Reactome)
	G-alpha(q) 11,14,15,Q:GTP	Arrow	R-HSA-400027 (Reactome)
G-alpha(q) 11,14,15,Q:GTP			R-HSA-400023 (Reactome)
	G-alpha(q)11,14,15,Q:G-beta:G-gamma	Arrow	R-HSA-399995 (Reactome)
	G-alpha(q)11,14,15,Q:G-beta:G-gamma	Arrow	R-HSA-416530 (Reactome)
G-alpha(q)11,14,15,Q:G-beta:G-gamma			R-HSA-400027 (Reactome)
G-alpha(q)11,14,15,Q:GDP:G-beta:G-gamma			R-HSA-399995 (Reactome)
G-alpha(q)11,14,15,Q:GDP:G-beta:G-gamma			R-HSA-416530 (Reactome)
G-alpha(s):GTP:G-beta:G-gamma			R-HSA-422320 (Reactome)
	G-beta:G-gamma (candidates)	Arrow	R-HSA-400037 (Reactome)
G-beta:G-gamma (candidates)		Arrow	R-HSA-400046 (Reactome)
	G-beta:G-gamma (candidates)	Arrow	R-HSA-422320 (Reactome)
G-beta:G-gamma (candidates)			R-HSA-400097 (Reactome)
	G-beta:G-gamma dimer	Arrow	R-HSA-825631 (Reactome)
	G-beta:G-gamma	Arrow	R-HSA-400027 (Reactome)
	G-protein alpha (s):GTP	Arrow	R-HSA-422320 (Reactome)
	G-protein alpha (s):GTP	Arrow	R-HSA-825631 (Reactome)
G-protein alpha (s):GTP			R-HSA-163617 (Reactome)
G-protein alpha (s):GTP			R-HSA-381704 (Reactome)
G-protein with G(s) alpha:GDP			R-HSA-825631 (Reactome)
	GA3P	Arrow	R-HSA-163764 (Reactome)
GA3P			R-HSA-163741 (Reactome)
GA3P			R-HSA-163751 (Reactome)
GCGR			R-HSA-163625 (Reactome)
	GDP	Arrow	R-HSA-381706 (Reactome)
	GDP	Arrow	R-HSA-381727 (Reactome)
	GDP	Arrow	R-HSA-399995 (Reactome)
	GDP	Arrow	R-HSA-400092 (Reactome)
	GDP	Arrow	R-HSA-416530 (Reactome)
	GDP	Arrow	R-HSA-825631 (Reactome)
	GLP-1:GLP-1R:Heterotrimeric G(s):GDP	Arrow	R-HSA-381612 (Reactome)
GLP-1:GLP-1R:Heterotrimeric G(s):GDP			R-HSA-381706 (Reactome)
	GLP-1:GLP-1R:Heterotrimeric G(s):GTP	Arrow	R-HSA-381706 (Reactome)
GLP-1R:Heterotrimeric G(s):GDP			R-HSA-381612 (Reactome)
GLUT1,2		mim-catalysis	R-HSA-499981 (Reactome)
GTP			R-HSA-381706 (Reactome)
GTP			R-HSA-381727 (Reactome)
GTP			R-HSA-399995 (Reactome)
GTP			R-HSA-400092 (Reactome)
GTP			R-HSA-416530 (Reactome)
GTP			R-HSA-825631 (Reactome)
	Glc	Arrow	R-HSA-499981 (Reactome)
Glc			R-HSA-499981 (Reactome)
	Glucagon:GCGR	Arrow	R-HSA-163625 (Reactome)
Glucagon:GCGR		mim-catalysis	R-HSA-825631 (Reactome)
Glucagon			R-HSA-163625 (Reactome)
	Gs-activated adenylate cyclase	Arrow	R-HSA-163617 (Reactome)
Gs-activated adenylate cyclase		mim-catalysis	R-HSA-164377 (Reactome)
H2O			R-HSA-163750 (Reactome)
H2O			R-HSA-399998 (Reactome)
I(1,4,5)P3		Arrow	R-HSA-169683 (Reactome)
	I(1,4,5)P3	Arrow	R-HSA-399998 (Reactome)
I(1,4,5)P3			R-HSA-169680 (Reactome)
	INS(57-87)	Arrow	R-HSA-265166 (Reactome)
INS(57-87)			R-HSA-265166 (Reactome)
IP3 receptor homotetramer			R-HSA-169680 (Reactome)
	ITPR:I(1,4,5)P3 tetramer	Arrow	R-HSA-169680 (Reactome)
ITPR:I(1,4,5)P3 tetramer		mim-catalysis	R-HSA-169683 (Reactome)
Inactive PP2A-ABdeltaC complex			R-HSA-163769 (Reactome)
	Insulin	Arrow	R-HSA-265166 (Reactome)
KCNJ11 tetramer:ABCC8:Mg2+:ADP tetramer			R-HSA-265682 (Reactome)
KCNJ11 tetramer:ABCC8:Mg2+:ADP tetramer		mim-catalysis	R-HSA-265682 (Reactome)
	KCNJ11:ATP tetramer:ABCC8 tetramer	Arrow	R-HSA-265682 (Reactome)
Ligands of FFAR1 (GPR40)			R-HSA-400434 (Reactome)
MARCKS			R-HSA-399978 (Reactome)
	MLXIPL	Arrow	R-HSA-163688 (Reactome)
	MLXIPL	Arrow	R-HSA-164056 (Reactome)
MLXIPL			R-HSA-163666 (Reactome)
MLXIPL			R-HSA-163672 (Reactome)
MLXIPL			R-HSA-163691 (Reactome)
MLX			R-HSA-163666 (Reactome)
	Mg2+:ADP	Arrow	R-HSA-265682 (Reactome)
	Muscarinic Acetylcholine Receptor M3:Acetylcholine Complex	Arrow	R-HSA-400012 (Reactome)
Muscarinic Acetylcholine Receptor M3:Acetylcholine Complex		mim-catalysis	R-HSA-399995 (Reactome)
	PFKFB1 dimer	Arrow	R-HSA-163750 (Reactome)
PFKFB1 dimer			R-HSA-163773 (Reactome)
PI(4,5)P2			R-HSA-399998 (Reactome)
	PKA catalytic subunit	Arrow	R-HSA-111925 (Reactome)
PKA catalytic subunit		Arrow	R-HSA-381644 (Reactome)
	PKA catalytic subunit	Arrow	R-HSA-381707 (Reactome)
PKA catalytic subunit		Arrow	R-HSA-381713 (Reactome)
PKA catalytic subunit		mim-catalysis	R-HSA-163676 (Reactome)
PKA catalytic subunit		mim-catalysis	R-HSA-163773 (Reactome)
PKA tetramer			R-HSA-111925 (Reactome)
PKA:AKAP79:IQGAP1 Complex			R-HSA-381707 (Reactome)
	PKLR-1	Arrow	R-HSA-163669 (Reactome)
	PLC beta1,2,3:G-alpha(q):GTP	Arrow	R-HSA-400023 (Reactome)
PLC beta1,2,3:G-alpha(q):GTP		mim-catalysis	R-HSA-399998 (Reactome)
PLC beta1,2,3			R-HSA-400023 (Reactome)
	PP2A-ABdeltaC complex	Arrow	R-HSA-163769 (Reactome)
PP2A-ABdeltaC complex		mim-catalysis	R-HSA-163688 (Reactome)
PP2A-ABdeltaC complex		mim-catalysis	R-HSA-163689 (Reactome)
PP2A-ABdeltaC complex		mim-catalysis	R-HSA-163750 (Reactome)
PP2A-ABdeltaC complex		mim-catalysis	R-HSA-164056 (Reactome)
	PPi	Arrow	R-HSA-164377 (Reactome)
	PPi	Arrow	R-HSA-381607 (Reactome)
PRKCA			R-HSA-400015 (Reactome)
	Pi	Arrow	R-HSA-163688 (Reactome)
	Pi	Arrow	R-HSA-163689 (Reactome)
	Pi	Arrow	R-HSA-163750 (Reactome)
	Pi	Arrow	R-HSA-164056 (Reactome)
	Potassium voltage-gated channels (beta cell, closed)	Arrow	R-HSA-381713 (Reactome)
Potassium voltage-gated channels (beta cell, open)			R-HSA-381713 (Reactome)
Potassium Channel, closed (pancreatic beta cell)			R-HSA-400063 (Reactome)
	Potassium Channel, open (pancreatic beta cell)	Arrow	R-HSA-400063 (Reactome)
Protein Kinase A, catalytic subunits		mim-catalysis	R-HSA-163672 (Reactome)
	Protein Kinase C, alpha type: DAG	Arrow	R-HSA-400015 (Reactome)
Protein Kinase C, alpha type: DAG		mim-catalysis	R-HSA-399978 (Reactome)
			R-HSA-111925 (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.
			R-HSA-163215 (Reactome)	A family of antiport, ATP-ADP translocases (SLC25A4,5,6), 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 (SLC25A4) is the heart/skeletal muscle form, isoform 2 (SLC25A5) is the fibroblast form and isoform 3 (SLC25A6) is the liver form. All isoforms exist as homodimers.
			R-HSA-163617 (Reactome)	G(s)-alpha:GTP binds to inactive adenylate cyclase, causing a conformational transition in adenylate cyclase exposing the catalytic site and activating it.
			R-HSA-163625 (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.
			R-HSA-163664 (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'.
			R-HSA-163666 (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'.
			R-HSA-163669 (Reactome)	At the end of this reaction, 1 molecule of 'pyruvate kinase, liver and RBC' is present. This reaction takes place in the 'nucleus'.
			R-HSA-163670 (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.
			R-HSA-163672 (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).
			R-HSA-163676 (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.
			R-HSA-163688 (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'.
			R-HSA-163689 (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'.
			R-HSA-163691 (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.
			R-HSA-163733 (Reactome)	At the end of this reaction, 1 molecule of 'Fatty acid synthase ' is present. This reaction takes place in the 'nucleus'.
			R-HSA-163741 (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).
			R-HSA-163743 (Reactome)	At the end of this reaction, 1 molecule of 'Acetyl-CoA carboxylase 2 ' is present. This reaction takes place in the 'nucleus'.
			R-HSA-163748 (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'.
			R-HSA-163750 (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'.
			R-HSA-163751 (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).
			R-HSA-163764 (Reactome)	Dimeric 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 and crystallographically (Banki et al. 1994; Thorell et al. 2000) and transaldolase deficiency in a patient has been correlated with a mutation in the TALDO1 gene (Verhoeven et al. 2001).
			R-HSA-163769 (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.
			R-HSA-163770 (Reactome)	At the end of this reaction, 1 molecule of 'citrate lyase monomer' is present. This reaction takes place in the 'nucleus'.
			R-HSA-163773 (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.
			R-HSA-164056 (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'.
			R-HSA-164151 (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).
			R-HSA-164377 (Reactome)	Activated adenylate cyclase associated with the plasma membrane catalyzes the reaction of cytosolic ATP to form 3',5'-cyclicAMP and pyrophosphate.
			R-HSA-164423 (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.
			R-HSA-169680 (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.
			R-HSA-169683 (Reactome)	IP3 promotes the release of intracellular calcium.
			R-HSA-265166 (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. 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.
			R-HSA-265645 (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.
			R-HSA-265682 (Reactome)	The beta-cell ATP-sensitive potassium channel (KATP channel) comprise the tetrameric ATP-sensitive inward rectifier potassium channel 11 (KCNJ11, Kir6.2) and the tetrameric channel regulator ATP-binding cassette sub-family C member 8 (ABCC8). When the ATP/ADP ratio is high, the KCNJ11 (Kir6.2) subunit binds ATP and the channel closes. Conversely, when the ADP:ATP ratio is high, the ABCC8 (SUR1) subunit binds magnesium-ADP and the channel is open. The KATP channels in the beta cell are inwardly rectifying (allowing potassium ions to pass out of 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. The antidiabetic activity of sulfonylurea drugs such as acetohexamide, tolbutamide, glipzide, glibenclamide, and glimepiride is due to their binding ABCC8 (SUR1) subunits and inhibiting potassium efflux.
			R-HSA-381607 (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.
			R-HSA-381608 (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.
			R-HSA-381612 (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.
			R-HSA-381644 (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.
			R-HSA-381668 (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.
			R-HSA-381704 (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.
			R-HSA-381706 (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).
			R-HSA-381707 (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.
			R-HSA-381713 (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.
			R-HSA-381727 (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.
			R-HSA-399978 (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.
			R-HSA-399995 (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.
			R-HSA-399998 (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.
			R-HSA-400012 (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).
			R-HSA-400015 (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.
			R-HSA-400023 (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.
			R-HSA-400027 (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.
			R-HSA-400037 (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.
			R-HSA-400046 (Reactome)	Closing (inhibition) of the L-type calcium channels in the plasma membrane prevents the flow of calcium ions across the membrane.
			R-HSA-400063 (Reactome)	ATP-sensitive Potassium channels open and allow an inward rectifying current of potassium ions to flow, reestablishing the resting potential of the cell.
			R-HSA-400071 (Reactome)	The pancreatic beta cell contains Alpha2A and Alpha2C Adrenergic Receptors. These are G-protein coupled receptors that can bind either adrenaline or noradrenaline.
			R-HSA-400092 (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.
			R-HSA-400097 (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.
			R-HSA-400434 (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).
			R-HSA-416530 (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.
			R-HSA-422320 (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.
			R-HSA-499981 (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.)
			R-HSA-5250209 (Reactome)	The complex between ADP-ribosylation factor-like protein 2-binding protein (ARL2BP aka BART) and GTP-bound ADP-ribosylation factor-like protein 2 (ARL2:GTP) is able to bind the ADP/ATP translocase 1 protein (SLC25A4 aka ANT1) at the mitochondrial inner membrane (Zhang et al. 2009, Bailey et al. 2009). ARL2 is essential for a number of mitochondrial functions, including mitochondrial morphology, motility and maintenance of ATP levels.
			R-HSA-5250210 (Reactome)	When ADP-ribosylation factor-like protein 2-binding protein (ARL2BP aka BART) binds GTP-bound ADP-ribosylation factor-like protein 2 (ARL2:GTP), the resultant complex can enter the mitochondrion via an unknown mechanism (Zhang et al. 2009, Bailey et al. 2009). Although ARL2 is a member of the ARF family of G proteins, it lacks the myristoylation at glycine-2 characteristic of that family and thus can move across the mitochondrial membrane into the intermembrane space (Sharer et al. 2002).
			R-HSA-5250217 (Reactome)	ADP-ribosylation factor-like protein 2 (ARL2) is a small (21kDa) GTPase protein that is able to bind GDP or GTP. It is implicated in a range of processes from trafficking processes to regulation of microtuble dynamics. ADP-ribosylation factor-like protein 2-binding protein (ARL2BP aka BART) is an effector protein that binds ARL2 (Zhang et al. 2009, Bailey et al. 2009). This binding is dependent on ARL2 being in its GTP-bound form.
			R-HSA-5672027 (Reactome)	A family of antiport, dimeric ATP-ADP translocases (SLC25A4,5,6), 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 with isoform 1 (SLC25A4, NAT1) being the heart/skeletal muscle form.
			R-HSA-825631 (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.
	R5P	Arrow	R-HSA-163741 (Reactome)
RAP1A:GDP			R-HSA-381727 (Reactome)
	RAP1A:GTP	Arrow	R-HSA-381727 (Reactome)
RAPGEF3:cAMP complex		Arrow	R-HSA-265682 (Reactome)
	RAPGEF3:cAMP complex	Arrow	R-HSA-381668 (Reactome)
RAPGEF3:cAMP complex		Arrow	R-HSA-381727 (Reactome)
RAPGEF3			R-HSA-381668 (Reactome)
RAPGEF4:cAMP Complex		Arrow	R-HSA-265682 (Reactome)
	RAPGEF4:cAMP Complex	Arrow	R-HSA-381608 (Reactome)
RAPGEF4:cAMP Complex		Arrow	R-HSA-381727 (Reactome)
RAPGEF4			R-HSA-381608 (Reactome)
	SH7P	Arrow	R-HSA-163764 (Reactome)
SH7P			R-HSA-163741 (Reactome)
SLC25A4			R-HSA-5250209 (Reactome)
SLC25A5,6 dimers		mim-catalysis	R-HSA-163215 (Reactome)
SNAP25			R-HSA-265166 (Reactome)
	SNARE Complex	Arrow	R-HSA-265166 (Reactome)
STK11		mim-catalysis	R-HSA-164151 (Reactome)
STX1A:STXBP1			R-HSA-265166 (Reactome)
	STXBP1	Arrow	R-HSA-265166 (Reactome)
SYT5			R-HSA-265166 (Reactome)
TALDO1 dimer		mim-catalysis	R-HSA-163764 (Reactome)
		TBar	R-HSA-265166 (Reactome)
VAMP2			R-HSA-265166 (Reactome)
Voltage-gated Calcium Channels (pancreatic beta cell)		mim-catalysis	R-HSA-265645 (Reactome)
	Voltage-gated Calcium Channels Type Cav1 (closed)	Arrow	R-HSA-400046 (Reactome)
Voltage-gated Calcium Channels Type Cav1 (closed)		TBar	R-HSA-265166 (Reactome)
Voltage-gated Calcium Channels Type Cav1 (open)			R-HSA-400046 (Reactome)
	XY5P	Arrow	R-HSA-163741 (Reactome)
	XY5P	Arrow	R-HSA-163751 (Reactome)
XY5P		Arrow	R-HSA-163769 (Reactome)
	Zn2+	Arrow	R-HSA-265166 (Reactome)
Zn2+		TBar	R-HSA-265682 (Reactome)
	cAMP:PKA regulatory subunit	Arrow	R-HSA-111925 (Reactome)
	cAMP:PKA:AKAP79:IQGAP1 Complex	Arrow	R-HSA-381707 (Reactome)
	cAMP	Arrow	R-HSA-164377 (Reactome)
	cAMP	Arrow	R-HSA-381607 (Reactome)
cAMP			R-HSA-111925 (Reactome)
cAMP			R-HSA-381608 (Reactome)
cAMP			R-HSA-381668 (Reactome)
cAMP			R-HSA-381707 (Reactome)
mature GLP-1			R-HSA-381612 (Reactome)
	p-4S-MARCKS	Arrow	R-HSA-399978 (Reactome)
	p-S196,T666-MLXIPL	Arrow	R-HSA-163676 (Reactome)
p-S196,T666-MLXIPL			R-HSA-163689 (Reactome)
	p-S568-MLXIPL	Arrow	R-HSA-163691 (Reactome)
p-S568-MLXIPL			R-HSA-164056 (Reactome)
	p-T666-MLXIPL	Arrow	R-HSA-163670 (Reactome)
	p-T666-MLXIPL	Arrow	R-HSA-163672 (Reactome)
	p-T666-MLXIPL	Arrow	R-HSA-163689 (Reactome)
	p-T666-MLXIPL	Arrow	R-HSA-164423 (Reactome)
p-T666-MLXIPL			R-HSA-163670 (Reactome)
p-T666-MLXIPL			R-HSA-163676 (Reactome)
p-T666-MLXIPL			R-HSA-163688 (Reactome)
p-T666-MLXIPL			R-HSA-164423 (Reactome)
	phosphoPFKFB1 dimer	Arrow	R-HSA-163773 (Reactome)
phosphoPFKFB1 dimer			R-HSA-163750 (Reactome)
transketolase dimer		mim-catalysis	R-HSA-163741 (Reactome)
transketolase dimer		mim-catalysis	R-HSA-163751 (Reactome)

Integration of energy metabolism (Homo sapiens)

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