KEGG   PATHWAY: pcw04911
Entry
pcw04911                    Pathway                                
Name
Insulin secretion - Phascolarctos cinereus (koala)
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
pcw04911  Insulin secretion
pcw04911

Other DBs
GO: 0030073
Organism
Phascolarctos cinereus (koala) [GN:pcw]
Gene
110192850  CAMK2A; calcium/calmodulin-dependent protein kinase type II subunit alpha isoform X1 [KO:K04515] [EC:2.7.11.17]
110192960  ADCYAP1R1; pituitary adenylate cyclase-activating polypeptide type I receptor [KO:K04587]
110194458  VAMP2; vesicle-associated membrane protein 2 [KO:K13504]
110194460  ATP1B2; sodium/potassium-transporting ATPase subunit beta-2 [KO:K01540]
110195440  PLCB3; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
110196478  RIMS2; regulating synaptic membrane exocytosis protein 2 isoform X1 [KO:K15297]
110196570  GPR119; glucose-dependent insulinotropic receptor [KO:K08424]
110197022  CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D isoform X1 [KO:K04851]
110197088  ADCYAP1; pituitary adenylate cyclase-activating polypeptide isoform X1 [KO:K05262]
110197190  INS; insulin [KO:K04526]
110197228  ATP1B3; sodium/potassium-transporting ATPase subunit beta-3 [KO:K01540]
110197384  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
110197489  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
110197533  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
110199423  ATF6B; LOW QUALITY PROTEIN: cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
110199765  ATP1B1; sodium/potassium-transporting ATPase subunit beta-1 [KO:K01540]
110199822  [KO:K04345] [EC:2.7.11.11]
110200046  ATP1B4; protein ATP1B4 [KO:K01540]
110201034  CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F [KO:K04853]
110201451  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
110201474  ADCY6; LOW QUALITY PROTEIN: adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
110201633  FFAR1; free fatty acid receptor 1 [KO:K04325]
110203112  ATP1A2; sodium/potassium-transporting ATPase subunit alpha-2 [KO:K01539] [EC:7.2.2.13]
110203115  [KO:K01539] [EC:7.2.2.13]
110203994  SLC2A2; solute carrier family 2, facilitated glucose transporter member 2 [KO:K07593]
110204386  KCNMB2; calcium-activated potassium channel subunit beta-2 isoform X1 [KO:K04938]
110204493  KCNMB3; LOW QUALITY PROTEIN: calcium-activated potassium channel subunit beta-3 [KO:K04939]
110205152  GNAS; guanine nucleotide-binding protein G(s) subunit alpha [KO:K04632]
110205453  CHRM3; muscarinic acetylcholine receptor M3 isoform X1 [KO:K04131]
110205802  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
110206215  SLC2A1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
110206409  GCK; glucokinase isoform X1 [KO:K12407] [EC:2.7.1.2]
110206523  ADCY3; LOW QUALITY PROTEIN: adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
110206572  CAMK2B; calcium/calmodulin-dependent protein kinase type II subunit beta isoform X1 [KO:K04515] [EC:2.7.11.17]
110207473  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
110207938  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
110207974  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
110208101  SNAP25; synaptosomal-associated protein 25 isoform X1 [KO:K18211]
110208122  ADCY5; LOW QUALITY PROTEIN: adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
110209126  CCK; cholecystokinin [KO:K05226]
110209926  PRKACB; cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
110210628  FXYD2; sodium/potassium-transporting ATPase subunit gamma isoform X1 [KO:K01538]
110210718  CCKAR; cholecystokinin receptor type A [KO:K04194]
110211063  KCNMB4; calcium-activated potassium channel subunit beta-4 isoform X1 [KO:K04941]
110211578  RAPGEF4; rap guanine nucleotide exchange factor 4 isoform X1 [KO:K04351]
110211588  ATF2; cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
110211994  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
110212102  KCNN3; LOW QUALITY PROTEIN: small conductance calcium-activated potassium channel protein 3 [KO:K04944]
110212313  KCNMB1; calcium-activated potassium channel subunit beta-1 [KO:K04937]
110213063  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
110214178  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
110214560  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
110214622  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
110214660  ADCY9; LOW QUALITY PROTEIN: adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
110215536  PDX1; pancreas/duodenum homeobox protein 1 [KO:K07594]
110215756  GIP; gastric inhibitory polypeptide [KO:K05258]
110216073  ADCY8; LOW QUALITY PROTEIN: adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
110216252  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
110217162  GLP1R; glucagon-like peptide 1 receptor [KO:K04581]
110217180  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
110217383  PCLO; LOW QUALITY PROTEIN: protein piccolo [KO:K16882]
110217820  RYR2; LOW QUALITY PROTEIN: ryanodine receptor 2 [KO:K04962]
110218307  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
110218623  CAMK2D; calcium/calmodulin-dependent protein kinase type II subunit delta isoform X1 [KO:K04515] [EC:2.7.11.17]
110218748  CACNA1C; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1C [KO:K04850]
110219354  ATP1A1; sodium/potassium-transporting ATPase subunit alpha-1 [KO:K01539] [EC:7.2.2.13]
110219570  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
110219967  KCNN4; intermediate conductance calcium-activated potassium channel protein 4 [KO:K04945]
110219984  TRPM4; transient receptor potential cation channel subfamily M member 4 [KO:K04979]
110220180  ATP1A3; LOW QUALITY PROTEIN: sodium/potassium-transporting ATPase subunit alpha-3 [KO:K01539] [EC:7.2.2.13]
110220182  PRKCG; LOW QUALITY PROTEIN: protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
110220436  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
110220711  GCG; glucagon isoform X1 [KO:K05259]
110220976  ABCC8; ATP-binding cassette sub-family C member 8 isoform X1 [KO:K05032]
110220980  KCNJ11; ATP-sensitive inward rectifier potassium channel 11 [KO:K05004]
110221325  STX1A; syntaxin-1A [KO:K04560]
110221426  KCNMA1; calcium-activated potassium channel subunit alpha-1 isoform X1 [KO:K04936]
110221437  CAMK2G; calcium/calmodulin-dependent protein kinase type II subunit gamma isoform X1 [KO:K04515] [EC:2.7.11.17]
110223284  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
110223412  GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
110223457  KCNN1; small conductance calcium-activated potassium channel protein 1 isoform X1 [KO:K04942]
110223504  RAB3A; ras-related protein Rab-3A [KO:K07882]
110223673  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
110223768  KCNN2; small conductance calcium-activated potassium channel protein 2 isoform X1 [KO:K04943]
110224036  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
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
pcw00020  Citrate cycle (TCA cycle)
pcw04020  Calcium signaling pathway
KO pathway
ko04911   

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