KEGG   PATHWAY: oaa04911
Entry
oaa04911                    Pathway                                
Name
Insulin secretion - Ornithorhynchus anatinus (platypus)
Description
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.
Class
Organismal Systems; Endocrine system
Pathway map
oaa04911  Insulin secretion
oaa04911

Other DBs
GO: 0030073
Organism
Ornithorhynchus anatinus (platypus) [GN:oaa]
Gene
100074548  SLC2A1; solute carrier family 2, facilitated glucose transporter member 1 isoform X1 [KO:K07299]
100086793  SLC2A2; solute carrier family 2, facilitated glucose transporter member 2 isoform X1 [KO:K07593]
100091176  hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
114815128  LOW QUALITY PROTEIN: hexokinase-4-like [KO:K12407] [EC:2.7.1.2]
100077318  TRPM4; LOW QUALITY PROTEIN: transient receptor potential cation channel subfamily M member 4 [KO:K04979]
100083795  sodium/potassium-transporting ATPase subunit alpha-2 isoform X1 [KO:K01539] [EC:7.2.2.13]
100088125  ATP1A3; LOW QUALITY PROTEIN: sodium/potassium-transporting ATPase subunit alpha-3 [KO:K01539] [EC:7.2.2.13]
100088592  ATP1A1; sodium/potassium-transporting ATPase subunit alpha-1 [KO:K01539] [EC:7.2.2.13]
103166927  sodium/potassium-transporting ATPase subunit alpha-2-like isoform X1 [KO:K01539] [EC:7.2.2.13]
100083662  ATP1B1; sodium/potassium-transporting ATPase subunit beta-1 [KO:K01540]
100078595  ATP1B3; sodium/potassium-transporting ATPase subunit beta-3 [KO:K01540]
100079079  ATP1B4; protein ATP1B4 isoform X1 [KO:K01540]
114808215  ATP1B2; sodium/potassium-transporting ATPase subunit beta-2 [KO:K01540]
100078637  ABCC8; ATP-binding cassette sub-family C member 8 isoform X1 [KO:K05032]
100078904  KCNJ11; LOW QUALITY PROTEIN: ATP-sensitive inward rectifier potassium channel 11 [KO:K05004]
100082618  CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C [KO:K04850]
100077296  CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851]
100075939  CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F [KO:K04853]
100093447  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
100089453  CAMK2G; calcium/calmodulin-dependent protein kinase type II subunit gamma isoform X1 [KO:K04515] [EC:2.7.11.17]
100079279  CAMK2A; calcium/calmodulin-dependent protein kinase type II subunit alpha isoform X1 [KO:K04515] [EC:2.7.11.17]
100074083  CAMK2D; calcium/calmodulin-dependent protein kinase type II subunit delta isoform X1 [KO:K04515] [EC:2.7.11.17]
100089905  CAMK2B; calcium/calmodulin-dependent protein kinase type II subunit beta isoform X1 [KO:K04515] [EC:2.7.11.17]
100079144  KCNMA1; calcium-activated potassium channel subunit alpha-1 isoform X10 [KO:K04936]
100082109  KCNU1; potassium channel subfamily U member 1 isoform X1 [KO:K05274]
100077694  KCNMB1; calcium-activated potassium channel subunit beta-1 [KO:K04937]
100074073  KCNMB2; calcium-activated potassium channel subunit beta-2 isoform X1 [KO:K04938]
100073915  KCNMB3; calcium-activated potassium channel subunit beta-3 [KO:K04939]
100079405  KCNMB4; calcium-activated potassium channel subunit beta-4 [KO:K04941]
103170479  KCNN1; LOW QUALITY PROTEIN: small conductance calcium-activated potassium channel protein 1 [KO:K04942]
100074996  KCNN2; small conductance calcium-activated potassium channel protein 2 [KO:K04943]
100093560  KCNN4; intermediate conductance calcium-activated potassium channel protein 4 [KO:K04945]
100082246  GCG; pro-glucagon isoform X1 [KO:K05259]
100076095  GLP1R; glucagon-like peptide 1 receptor [KO:K04581]
114814984  gastric inhibitory polypeptide [KO:K05258]
100081227  ADCYAP1; pituitary adenylate cyclase-activating polypeptide isoform X1 [KO:K05262]
100092092  ADCYAP1R1; pituitary adenylate cyclase-activating polypeptide type I receptor isoform X1 [KO:K04587]
100080392  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoform X1 [KO:K04632]
103168601  ADCY1; LOW QUALITY PROTEIN: adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
100089708  ADCY2; adenylate cyclase type 2 isoform X1 [KO:K08042] [EC:4.6.1.1]
100085901  ADCY3; LOW QUALITY PROTEIN: adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
103168714  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
114811232  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
100081118  ADCY6; adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
100076221  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
100077908  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
100080569  ADCY9; adenylate cyclase type 9 isoform X1 [KO:K08049] [EC:4.6.1.1]
100078846  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
100088079  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
100093310  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
100077942  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
100089902  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
100078176  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
100092528  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
100076562  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
103165821  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
100080655  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X2 [KO:K09047]
100080771  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
100090417  PDX1; pancreas/duodenum homeobox protein 1 [KO:K07594]
114810063  INS; insulin [KO:K04526]
100084234  RAPGEF4; rap guanine nucleotide exchange factor 4 isoform X1 [KO:K04351]
100078919  RIMS2; regulating synaptic membrane exocytosis protein 2 isoform X1 [KO:K15297]
100074697  PCLO; protein piccolo [KO:K16882]
100080262  RAB3A; ras-related protein Rab-3A [KO:K07882]
100089323  CCK; cholecystokinin [KO:K05226]
107547241  CCKAR; cholecystokinin receptor type A [KO:K04194]
100084007  CHRM3; muscarinic acetylcholine receptor M3 isoform X2 [KO:K04131]
100080691  guanine nucleotide-binding protein G(q) subunit alpha isoform X1 [KO:K04634]
100084804  GNA11; guanine nucleotide-binding protein subunit alpha-11 isoform X1 [KO:K04635]
114808753  guanine nucleotide-binding protein subunit alpha-11-like [KO:K04635]
100078508  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
100084272  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
100081349  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
100086536  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
100088770  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
100084273  RYR2; LOW QUALITY PROTEIN: ryanodine receptor 2 [KO:K04962]
100074858  vesicle-associated membrane protein 2 [KO:K13504]
114808207  VAMP2; vesicle-associated membrane protein 2 [KO:K13504]
103169086  STX1A; LOW QUALITY PROTEIN: syntaxin-1A [KO:K04560]
100078539  SNAP25; synaptosomal-associated protein 25 isoform X1 [KO:K18211]
100076473  synaptosomal-associated protein 25-like [KO:K18211]
100079107  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
100074181  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
100085442  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
Compound
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
Reference
PMID:20551594
  Authors
Seino S, Shibasaki T, Minami K
  Title
Pancreatic beta-cell signaling: toward better understanding of diabetes and its treatment.
  Journal
Proc Jpn Acad Ser B Phys Biol Sci 86:563-77 (2010)
DOI:10.2183/pjab.86.563
Reference
PMID:20225132
  Authors
Jitrapakdee S, Wutthisathapornchai A, Wallace JC, MacDonald MJ
  Title
Regulation of insulin secretion: role of mitochondrial signalling.
  Journal
Diabetologia 53:1019-32 (2010)
DOI:10.1007/s00125-010-1685-0
Reference
PMID:22974438
  Authors
Rorsman P, Braun M
  Title
Regulation of insulin secretion in human pancreatic islets.
  Journal
Annu Rev Physiol 75:155-79 (2013)
DOI:10.1146/annurev-physiol-030212-183754
Reference
PMID:9715374
  Authors
Jones PM, Persaud SJ
  Title
Protein kinases, protein phosphorylation, and the regulation of insulin secretion from pancreatic beta-cells.
  Journal
Endocr Rev 19:429-61 (1998)
DOI:10.1210/edrv.19.4.0339
Reference
PMID:21934040
  Authors
MacDonald PE
  Title
Signal integration at the level of ion channel and exocytotic function in pancreatic beta-cells.
  Journal
Am J Physiol Endocrinol Metab 301:E1065-9 (2011)
DOI:10.1152/ajpendo.00426.2011
Reference
PMID:9914469
  Authors
Lang J
  Title
Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrine secretion.
  Journal
Eur J Biochem 259:3-17 (1999)
DOI:10.1046/j.1432-1327.1999.00043.x
Reference
PMID:10605628
  Authors
Kieffer TJ, Habener JF
  Title
The glucagon-like peptides.
  Journal
Endocr Rev 20:876-913 (1999)
DOI:10.1210/edrv.20.6.0385
Reference
PMID:19036624
  Authors
Girard J
  Title
The incretins: from the concept to their use in the treatment of type 2 diabetes. Part A: incretins: concept and physiological functions.
  Journal
Diabetes Metab 34:550-9 (2008)
DOI:10.1016/j.diabet.2008.09.001
Reference
PMID:15655710
  Authors
Holz GG
  Title
New insights concerning the glucose-dependent insulin secretagogue action of glucagon-like peptide-1 in pancreatic beta-cells.
  Journal
Horm Metab Res 36:787-94 (2004)
DOI:10.1055/s-2004-826165
Reference
PMID:15271645
  Authors
Holst JJ, Gromada J
  Title
Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans.
  Journal
Am J Physiol Endocrinol Metab 287:E199-206 (2004)
DOI:10.1152/ajpendo.00545.2003
Reference
PMID:17306374
  Authors
Doyle ME, Egan JM
  Title
Mechanisms of action of glucagon-like peptide 1 in the pancreas.
  Journal
Pharmacol Ther 113:546-93 (2007)
DOI:10.1016/j.pharmthera.2006.11.007
Reference
PMID:19074620
  Authors
Kim W, Egan JM
  Title
The role of incretins in glucose homeostasis and diabetes treatment.
  Journal
Pharmacol Rev 60:470-512 (2008)
DOI:10.1124/pr.108.000604
Reference
PMID:19817800
  Authors
Seino S, Takahashi H, Fujimoto W, Shibasaki T
  Title
Roles of cAMP signalling in insulin granule exocytosis.
  Journal
Diabetes Obes Metab 11 Suppl 4:180-8 (2009)
DOI:10.1111/j.1463-1326.2009.01108.x
Reference
PMID:22970724
  Authors
Tengholm A
  Title
Cyclic AMP dynamics in the pancreatic beta-cell.
  Journal
Ups J Med Sci 117:355-69 (2012)
DOI:10.3109/03009734.2012.724732
Reference
PMID:14693691
  Authors
Holz GG
  Title
Epac: A new cAMP-binding protein in support of glucagon-like peptide-1 receptor-mediated signal transduction in the pancreatic beta-cell.
  Journal
Diabetes 53:5-13 (2004)
DOI:10.2337/diabetes.53.1.5
Reference
PMID:20055708
  Authors
Gloerich M, Bos JL
  Title
Epac: defining a new mechanism for cAMP action.
  Journal
Annu Rev Pharmacol Toxicol 50:355-75 (2010)
DOI:10.1146/annurev.pharmtox.010909.105714
Reference
PMID:17084085
  Authors
Bos JL
  Title
Epac proteins: multi-purpose cAMP targets.
  Journal
Trends Biochem Sci 31:680-6 (2006)
DOI:10.1016/j.tibs.2006.10.002
Reference
PMID:11522660
  Authors
Filipsson K, Kvist-Reimer M, Ahren B
  Title
The neuropeptide pituitary adenylate cyclase-activating polypeptide and islet function.
  Journal
Diabetes 50:1959-69 (2001)
DOI:10.2337/diabetes.50.9.1959
Reference
PMID:19817784
  Authors
Kebede MA, Alquier T, Latour MG, Poitout V
  Title
Lipid receptors and islet function: therapeutic implications?
  Journal
Diabetes Obes Metab 11 Suppl 4:10-20 (2009)
DOI:10.1111/j.1463-1326.2009.01114.x
Reference
PMID:19660440
  Authors
Morgan NG, Dhayal S
  Title
G-protein coupled receptors mediating long chain fatty acid signalling in the pancreatic beta-cell.
  Journal
Biochem Pharmacol 78:1419-27 (2009)
DOI:10.1016/j.bcp.2009.07.020
Related
pathway
oaa00020  Citrate cycle (TCA cycle)
oaa04020  Calcium signaling pathway
KO pathway
ko04911   
LinkDB

DBGET integrated database retrieval system