KEGG   PATHWAY: ray04911
ray04911                    Pathway                                

Insulin secretion - Rousettus aegyptiacus (Egyptian rousette)
Pancreatic beta cells are specialised endocrine cells that continuously sense the levels of blood sugar and other fuels and, in response, secrete insulin to maintain normal fuel homeostasis. Glucose-induced insulin secretion and its potentiation constitute the principal mechanism of insulin release. Glucose is transported by the glucose transporter (GLUT) into the pancreatic beta-cell. Metabolism of glucose generates ATP, which inhibits ATP-sensitive K+ channels and causes voltage-dependent Ca2+ influx. Elevation of [Ca2+]i triggers exocytotic release of insulin granules. Insulin secretion is further regulated by several hormones and neurotransmitters. Peptide hormones, such as glucagon-like peptide 1 (GLP-1), increase cAMP levels and thereby potentiate insulin secretion via the combined action of PKA and Epac2. Achetylcholine (ACh), a major parasympathetic neurotransmitter, binds to Gq-coupled receptors and activates phospholipase C- (PLC-), and the stimulatory effects involve activation of protein kinase C (PKC), which stimulates exocytosis. In addition, ACh mobilizes intracellular Ca2+ by activation of IP3 receptors.
Organismal Systems; Endocrine system
Pathway map
ray04911  Insulin secretion

Other DBs
GO: 0030073
Rousettus aegyptiacus (Egyptian rousette) [GN:ray]
107508288  SLC2A1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
107501411  SLC2A2; solute carrier family 2, facilitated glucose transporter member 2 isoform X1 [KO:K07593]
107512383  GCK; glucokinase isoform X1 [KO:K12407] [EC:]
107498826  TRPM4; transient receptor potential cation channel subfamily M member 4 isoform X1 [KO:K04979]
107499819  ATP1A1; sodium/potassium-transporting ATPase subunit alpha-1 isoform X1 [KO:K01539] [EC:]
107502600  ATP1A3; sodium/potassium-transporting ATPase subunit alpha-3 [KO:K01539] [EC:]
107507949  ATP1A2; sodium/potassium-transporting ATPase subunit alpha-2 isoform X1 [KO:K01539] [EC:]
107507966  ATP1A4; sodium/potassium-transporting ATPase subunit alpha-4 [KO:K01539] [EC:]
107509410  ATP1B3; LOW QUALITY PROTEIN: sodium/potassium-transporting ATPase subunit beta-3 [KO:K01540]
107512755  ATP1B1; sodium/potassium-transporting ATPase subunit beta-1 [KO:K01540]
107515690  ATP1B2; sodium/potassium-transporting ATPase subunit beta-2 [KO:K01540]
107498709  ATP1B4; protein ATP1B4 isoform X1 [KO:K01540]
107505043  FXYD2; sodium/potassium-transporting ATPase subunit gamma isoform X1 [KO:K01538]
107508030  ABCC8; ATP-binding cassette sub-family C member 8 isoform X1 [KO:K05032]
107508032  KCNJ11; ATP-sensitive inward rectifier potassium channel 11 [KO:K05004]
107500540  CACNA1C; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1C [KO:K04850]
107516535  CACNA1D; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851]
107514999  CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853]
107513628  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
107510894  CAMK2D; calcium/calmodulin-dependent protein kinase type II subunit delta isoform X1 [KO:K04515] [EC:]
107512385  CAMK2B; calcium/calmodulin-dependent protein kinase type II subunit beta isoform X1 [KO:K04515] [EC:]
107497167  CAMK2A; calcium/calmodulin-dependent protein kinase type II subunit alpha isoform X1 [KO:K04515] [EC:]
107498266  CAMK2G; calcium/calmodulin-dependent protein kinase type II subunit gamma isoform X1 [KO:K04515] [EC:]
107518064  KCNMA1; calcium-activated potassium channel subunit alpha-1 isoform X1 [KO:K04936]
107515946  KCNU1; LOW QUALITY PROTEIN: potassium channel subfamily U member 1 [KO:K05274]
107518473  KCNMB1; calcium-activated potassium channel subunit beta-1 [KO:K04937]
107517571  KCNMB2; calcium-activated potassium channel subunit beta-2 [KO:K04938]
107518045  KCNMB3; calcium-activated potassium channel subunit beta-3 isoform X1 [KO:K04939]
107514514  KCNMB4; calcium-activated potassium channel subunit beta-4 [KO:K04941]
107521731  KCNN1; small conductance calcium-activated potassium channel protein 1 isoform X1 [KO:K04942]
107512127  KCNN2; small conductance calcium-activated potassium channel protein 2 isoform X1 [KO:K04943]
107504719  KCNN3; small conductance calcium-activated potassium channel protein 3 isoform X1 [KO:K04944]
107512308  KCNN4; intermediate conductance calcium-activated potassium channel protein 4 isoform X1 [KO:K04945]
107511730  GCG; glucagon isoform X1 [KO:K05259]
107515469  GLP1R; LOW QUALITY PROTEIN: glucagon-like peptide 1 receptor [KO:K04581]
107517580  GIP; gastric inhibitory polypeptide [KO:K05258]
107514777  GPR119; glucose-dependent insulinotropic receptor [KO:K08424]
107520585  ADCYAP1; pituitary adenylate cyclase-activating polypeptide isoform X1 [KO:K05262]
107499553  ADCYAP1R1; pituitary adenylate cyclase-activating polypeptide type I receptor isoform X1 [KO:K04587]
107500068  neuroendocrine secretory protein 55-like [KO:K04632]
107500067  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoform X1 [KO:K04632]
107512406  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:]
107502700  ADCY2; LOW QUALITY PROTEIN: adenylate cyclase type 2 [KO:K08042] [EC:]
107498506  ADCY3; LOW QUALITY PROTEIN: adenylate cyclase type 3 [KO:K08043] [EC:]
107498014  ADCY4; LOW QUALITY PROTEIN: adenylate cyclase type 4 [KO:K08044] [EC:]
107518038  ADCY5; LOW QUALITY PROTEIN: adenylate cyclase type 5 [KO:K08045] [EC:]
107514224  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:]
107512248  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:]
107497689  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:]
107521680  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:]
107519437  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:]
107511590  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:]
107505169  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
107504977  ATF2; cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
107500816  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
107509179  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
107502779  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
107511864  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
107510647  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
107499057  CREB3L2; LOW QUALITY PROTEIN: cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
107505683  CREB5; cyclic AMP-responsive element-binding protein 5 [KO:K09047]
107498439  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
107516508  PDX1; pancreas/duodenum homeobox protein 1 [KO:K07594]
107513269  INS; insulin isoform X1 [KO:K04526]
107505164  RAPGEF4; rap guanine nucleotide exchange factor 4 isoform X1 [KO:K04351]
107512205  RIMS2; regulating synaptic membrane exocytosis protein 2 isoform X1 [KO:K15297]
107519744  PCLO; LOW QUALITY PROTEIN: protein piccolo [KO:K16882]
107521651  RAB3A; ras-related protein Rab-3A [KO:K07882]
107519989  CCK; cholecystokinin [KO:K05226]
107505449  CCKAR; cholecystokinin receptor type A [KO:K04194]
107502405  CHRM3; muscarinic acetylcholine receptor M3 [KO:K04131]
107497635  FFAR1; free fatty acid receptor 1 [KO:K04325]
107517194  GNAQ; LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
107520124  GNA11; LOW QUALITY PROTEIN: guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
107506114  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:]
107519930  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:]
107497081  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:]
107514464  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:]
107511965  ITPR3; LOW QUALITY PROTEIN: inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
107520024  RYR2; LOW QUALITY PROTEIN: ryanodine receptor 2 [KO:K04962]
107515669  VAMP2; vesicle-associated membrane protein 2 isoform X1 [KO:K13504]
107511813  STX1A; syntaxin-1A [KO:K04560]
107507100  SNAP25; synaptosomal-associated protein 25 isoform X1 [KO:K18211]
107510307  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:]
107516091  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:]
107503061  PRKCG; protein kinase C gamma type isoform X1 [KO:K19663] [EC:]
C00002  ATP
C00022  Pyruvate
C00031  D-Glucose
C00076  Calcium cation
C00092  D-Glucose 6-phosphate
C00162  Fatty acid
C00165  Diacylglycerol
C00238  Potassium cation
C00575  3',5'-Cyclic AMP
C01245  D-myo-Inositol 1,4,5-trisphosphate
C01330  Sodium cation
C01996  Acetylcholine
Seino S, Shibasaki T, Minami K
Pancreatic beta-cell signaling: toward better understanding of diabetes and its treatment.
Proc Jpn Acad Ser B Phys Biol Sci 86:563-77 (2010)
Jitrapakdee S, Wutthisathapornchai A, Wallace JC, MacDonald MJ
Regulation of insulin secretion: role of mitochondrial signalling.
Diabetologia 53:1019-32 (2010)
Rorsman P, Braun M
Regulation of insulin secretion in human pancreatic islets.
Annu Rev Physiol 75:155-79 (2013)
Jones PM, Persaud SJ
Protein kinases, protein phosphorylation, and the regulation of insulin secretion from pancreatic beta-cells.
Endocr Rev 19:429-61 (1998)
MacDonald PE
Signal integration at the level of ion channel and exocytotic function in pancreatic beta-cells.
Am J Physiol Endocrinol Metab 301:E1065-9 (2011)
Lang J
Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrine secretion.
Eur J Biochem 259:3-17 (1999)
Kieffer TJ, Habener JF
The glucagon-like peptides.
Endocr Rev 20:876-913 (1999)
Girard J
The incretins: from the concept to their use in the treatment of type 2 diabetes. Part A: incretins: concept and physiological functions.
Diabetes Metab 34:550-9 (2008)
Holz GG
New insights concerning the glucose-dependent insulin secretagogue action of glucagon-like peptide-1 in pancreatic beta-cells.
Horm Metab Res 36:787-94 (2004)
Holst JJ, Gromada J
Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans.
Am J Physiol Endocrinol Metab 287:E199-206 (2004)
Doyle ME, Egan JM
Mechanisms of action of glucagon-like peptide 1 in the pancreas.
Pharmacol Ther 113:546-93 (2007)
Kim W, Egan JM
The role of incretins in glucose homeostasis and diabetes treatment.
Pharmacol Rev 60:470-512 (2008)
Seino S, Takahashi H, Fujimoto W, Shibasaki T
Roles of cAMP signalling in insulin granule exocytosis.
Diabetes Obes Metab 11 Suppl 4:180-8 (2009)
Tengholm A
Cyclic AMP dynamics in the pancreatic beta-cell.
Ups J Med Sci 117:355-69 (2012)
Holz GG
Epac: A new cAMP-binding protein in support of glucagon-like peptide-1 receptor-mediated signal transduction in the pancreatic beta-cell.
Diabetes 53:5-13 (2004)
Gloerich M, Bos JL
Epac: defining a new mechanism for cAMP action.
Annu Rev Pharmacol Toxicol 50:355-75 (2010)
Bos JL
Epac proteins: multi-purpose cAMP targets.
Trends Biochem Sci 31:680-6 (2006)
Filipsson K, Kvist-Reimer M, Ahren B
The neuropeptide pituitary adenylate cyclase-activating polypeptide and islet function.
Diabetes 50:1959-69 (2001)
Kebede MA, Alquier T, Latour MG, Poitout V
Lipid receptors and islet function: therapeutic implications?
Diabetes Obes Metab 11 Suppl 4:10-20 (2009)
Morgan NG, Dhayal S
G-protein coupled receptors mediating long chain fatty acid signalling in the pancreatic beta-cell.
Biochem Pharmacol 78:1419-27 (2009)
ray00020  Citrate cycle (TCA cycle)
ray04020  Calcium signaling pathway
ray05211  Renal cell carcinoma
KO pathway

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