KEGG   PATHWAY: aml04911
Entry
aml04911                    Pathway                                
Name
Insulin secretion - Ailuropoda melanoleuca (giant panda)
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
aml04911  Insulin secretion
aml04911

Other DBs
GO: 0030073
Organism
Ailuropoda melanoleuca (giant panda) [GN:aml]
Gene
100463582  KCNMB1; calcium-activated potassium channel subunit beta-1 isoform X1 [KO:K04937]
100463833  KCNMB4; calcium-activated potassium channel subunit beta-4 isoform X2 [KO:K04941]
100464853  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
100465232  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
100465438  GLP1R; glucagon-like peptide 1 receptor isoform X1 [KO:K04581]
100465448  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
100465931  GCG; glucagon isoform X2 [KO:K05259]
100466256  CAMK2D; calcium/calmodulin-dependent protein kinase type II subunit delta isoform X5 [KO:K04515] [EC:2.7.11.17]
100466965  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
100467700  CACNA1D; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851]
100468088  FFAR1; free fatty acid receptor 1 [KO:K04325]
100468252  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X2 [KO:K04345] [EC:2.7.11.11]
100468266  ATP1B2; sodium/potassium-transporting ATPase subunit beta-2 [KO:K01540]
100468357  KCNN4; intermediate conductance calcium-activated potassium channel protein 4 [KO:K04945]
100468661  CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853]
100469080  ATP1B1; sodium/potassium-transporting ATPase subunit beta-1 [KO:K01540]
100469231  [KO:K04632]
100469579  TRPM4; transient receptor potential cation channel subfamily M member 4 isoform X1 [KO:K04979]
100469628  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
100469689  GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
100469796  [KO:K01538]
100470867  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
100471032  STX1A; syntaxin-1A [KO:K04560]
100471164  ADCY3; adenylate cyclase type 3 isoform X2 [KO:K08043] [EC:4.6.1.1]
100471458  CCKAR; cholecystokinin receptor type A [KO:K04194]
100471509  KCNU1; LOW QUALITY PROTEIN: potassium channel subfamily U member 1 [KO:K05274]
100471747  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
100471940  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
100472023  ADCYAP1; pituitary adenylate cyclase-activating polypeptide [KO:K05262]
100472104  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
100472777  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
100472835  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S isoform X1 [KO:K04857]
100473013  SNAP25; synaptosomal-associated protein 25 isoform X2 [KO:K18211]
100473195  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
100473263  KCNMA1; calcium-activated potassium channel subunit alpha-1 isoform X23 [KO:K04936]
100473680  [KO:K04632]
100474121  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
100474135  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X2 [KO:K04450]
100474260  KCNN1; small conductance calcium-activated potassium channel protein 1 isoform X1 [KO:K04942]
100474261  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
100474459  CAMK2G; calcium/calmodulin-dependent protein kinase type II subunit gamma isoform X3 [KO:K04515] [EC:2.7.11.17]
100474701  RIMS2; regulating synaptic membrane exocytosis protein 2 isoform X39 [KO:K15297]
100474779  PLCB2; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
100475467  CAMK2A; calcium/calmodulin-dependent protein kinase type II subunit alpha isoform X2 [KO:K04515] [EC:2.7.11.17]
100475715  GPR119; glucose-dependent insulinotropic receptor [KO:K08424]
100475738  GCK; hexokinase-4 isoform X2 [KO:K12407] [EC:2.7.1.2]
100475889  SLC2A2; solute carrier family 2, facilitated glucose transporter member 2 [KO:K07593]
100476017  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X2 [KO:K09049]
100476146  KCNN2; small conductance calcium-activated potassium channel protein 2 [KO:K04943]
100476284  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
100476495  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
100476576  RYR2; LOW QUALITY PROTEIN: ryanodine receptor 2 [KO:K04962]
100476922  ADCY6; adenylate cyclase type 6 isoform X2 [KO:K08046] [EC:4.6.1.1]
100476930  SLC2A1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
100477326  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
100477337  CCK; cholecystokinin [KO:K05226]
100477377  RAB3A; ras-related protein Rab-3A [KO:K07882]
100477585  ATP1A3; sodium/potassium-transporting ATPase subunit alpha-3 isoform X1 [KO:K01539] [EC:7.2.2.13]
100477711  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
100477989  ATP1A1; sodium/potassium-transporting ATPase subunit alpha-1 isoform X1 [KO:K01539] [EC:7.2.2.13]
100478007  PRKCB; protein kinase C beta type isoform X2 [KO:K19662] [EC:2.7.11.13]
100478243  CAMK2B; calcium/calmodulin-dependent protein kinase type II subunit beta [KO:K04515] [EC:2.7.11.17]
100479164  ADCYAP1R1; pituitary adenylate cyclase-activating polypeptide type I receptor isoform X1 [KO:K04587]
100479348  VAMP2; vesicle-associated membrane protein 2 [KO:K13504]
100479715  CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C isoform X3 [KO:K04850]
100480097  RAPGEF4; rap guanine nucleotide exchange factor 4 isoform X1 [KO:K04351]
100480112  ABCC8; ATP-binding cassette sub-family C member 8 isoform X6 [KO:K05032]
100480603  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:3.1.4.11]
100480641  [KO:K01539] [EC:7.2.2.13]
100480890  ATP1A4; sodium/potassium-transporting ATPase subunit alpha-4 [KO:K01539] [EC:7.2.2.13]
100481012  ATP1B4; protein ATP1B4 isoform X3 [KO:K01540]
100481356  KCNN3; small conductance calcium-activated potassium channel protein 3 isoform X2 [KO:K04944]
100481755  PLCB1; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
100482116  KCNJ11; ATP-sensitive inward rectifier potassium channel 11 [KO:K05004]
100482519  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
100483215  PDX1; pancreas/duodenum homeobox protein 1 [KO:K07594]
100483432  INS; insulin isoform X2 [KO:K04526]
100483482  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
100483582  GIP; gastric inhibitory polypeptide [KO:K05258]
100483809  KCNMB2; calcium-activated potassium channel subunit beta-2 isoform X2 [KO:K04938]
100484063  KCNMB3; calcium-activated potassium channel subunit beta-3 isoform X1 [KO:K04939]
100484531  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
100484596  ATP1B3; sodium/potassium-transporting ATPase subunit beta-3 [KO:K01540]
100484719  PRKCG; protein kinase C gamma type isoform X1 [KO:K19663] [EC:2.7.11.13]
105236987  PCLO; LOW QUALITY PROTEIN: protein piccolo [KO:K16882]
109488507  CHRM3; muscarinic acetylcholine receptor M3 isoform X1 [KO:K04131]
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
aml00020  Citrate cycle (TCA cycle)
aml04020  Calcium signaling pathway
KO pathway
ko04911   

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