KEGG   PATHWAY: eai04911
Entry
eai04911                    Pathway                                
Name
Insulin secretion - Equus asinus (ass)
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
eai04911  Insulin secretion
eai04911

Other DBs
GO: 0030073
Organism
Equus asinus (ass) [GN:eai]
Gene
106847800  SLC2A1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
106847542  SLC2A2; solute carrier family 2, facilitated glucose transporter member 2 [KO:K07593]
106822865  hexokinase-4 [KO:K12407] [EC:2.7.1.2]
106838280  TRPM4; transient receptor potential cation channel subfamily M member 4 isoform X1 [KO:K04979]
106847933  ATP1A3; sodium/potassium-transporting ATPase subunit alpha-3 isoform X1 [KO:K01539] [EC:7.2.2.13]
106835689  ATP1A1; sodium/potassium-transporting ATPase subunit alpha-1 isoform X2 [KO:K01539] [EC:7.2.2.13]
106835754  ATP1A4; sodium/potassium-transporting ATPase subunit alpha-4 isoform X1 [KO:K01539] [EC:7.2.2.13]
106835755  sodium/potassium-transporting ATPase subunit alpha-2 [KO:K01539] [EC:7.2.2.13]
106824855  ATP1B4; protein ATP1B4 isoform X3 [KO:K01540]
106841565  ATP1B1; sodium/potassium-transporting ATPase subunit beta-1 [KO:K01540]
106844216  ATP1B2; sodium/potassium-transporting ATPase subunit beta-2 isoform X1 [KO:K01540]
106838143  ATP1B3; sodium/potassium-transporting ATPase subunit beta-3 [KO:K01540]
106840265  FXYD2; sodium/potassium-transporting ATPase subunit gamma isoform X1 [KO:K01538]
106835490  ABCC8; ATP-binding cassette sub-family C member 8 isoform X1 [KO:K05032]
106835482  KCNJ11; ATP-sensitive inward rectifier potassium channel 11 [KO:K05004]
106839455  CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C isoform X1 [KO:K04850]
106822066  CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D isoform X8 [KO:K04851]
106826963  CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853]
106823553  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S isoform X3 [KO:K04857]
106843233  CAMK2D; calcium/calmodulin-dependent protein kinase type II subunit delta isoform X1 [KO:K04515] [EC:2.7.11.17]
106843543  CAMK2G; calcium/calmodulin-dependent protein kinase type II subunit gamma isoform X1 [KO:K04515] [EC:2.7.11.17]
106822866  CAMK2B; calcium/calmodulin-dependent protein kinase type II subunit beta isoform X1 [KO:K04515] [EC:2.7.11.17]
106838495  CAMK2A; calcium/calmodulin-dependent protein kinase type II subunit alpha isoform X1 [KO:K04515] [EC:2.7.11.17]
106828419  KCNMA1; calcium-activated potassium channel subunit alpha-1 isoform X12 [KO:K04936]
106837690  KCNU1; potassium channel subfamily U member 1 isoform X1 [KO:K05274]
106837364  KCNMB1; calcium-activated potassium channel subunit beta-1 [KO:K04937]
106829319  KCNMB2; calcium-activated potassium channel subunit beta-2 isoform X1 [KO:K04938]
106829315  KCNMB3; calcium-activated potassium channel subunit beta-3 isoform X2 [KO:K04939]
106842192  KCNMB4; calcium-activated potassium channel subunit beta-4 [KO:K04941]
106824991  KCNN1; small conductance calcium-activated potassium channel protein 1 isoform X1 [KO:K04942]
106832185  KCNN2; small conductance calcium-activated potassium channel protein 2 isoform X1 [KO:K04943]
106828522  KCNN3; small conductance calcium-activated potassium channel protein 3 isoform X2 [KO:K04944]
106848402  KCNN4; intermediate conductance calcium-activated potassium channel protein 4 isoform X1 [KO:K04945]
106843192  GCG; pro-glucagon isoform X1 [KO:K05259]
106824607  GLP1R; glucagon-like peptide 1 receptor [KO:K04581]
106826251  gastric inhibitory polypeptide [KO:K05258]
106838741  GPR119; glucose-dependent insulinotropic receptor [KO:K08424]
106845113  ADCYAP1; pituitary adenylate cyclase-activating polypeptide isoform X1 [KO:K05262]
106831070  ADCYAP1R1; pituitary adenylate cyclase-activating polypeptide type I receptor isoform X1 [KO:K04587]
106825087  guanine nucleotide-binding protein G(s) subunit alpha isoform X1 [KO:K04632]
106825115  neuroendocrine secretory protein 55 [KO:K04632]
106822932  ADCY1; adenylate cyclase type 1 isoform X1 [KO:K08041] [EC:4.6.1.1]
106823001  ADCY2; adenylate cyclase type 2 isoform X1 [KO:K08042] [EC:4.6.1.1]
106841140  ADCY3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
106848607  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
106823728  ADCY5; LOW QUALITY PROTEIN: adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
106836825  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
106824126  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
106824833  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
106826021  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
106844316  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
106824036  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
106828159  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
106837905  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X2 [KO:K04450]
106842437  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
106846249  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X2 [KO:K09048]
106843990  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
106846981  CREB3; LOW QUALITY PROTEIN: cyclic AMP-responsive element-binding protein 3 [KO:K09048]
106829982  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
106832323  CREB3L3; LOW QUALITY PROTEIN: cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
106831046  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
106831009  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
106832925  PDX1; pancreas/duodenum homeobox protein 1 [KO:K07594]
106834741  RAPGEF4; rap guanine nucleotide exchange factor 4 isoform X2 [KO:K04351]
106821779  RIMS2; regulating synaptic membrane exocytosis protein 2 isoform X30 [KO:K15297]
106832426  PCLO; protein piccolo [KO:K16882]
106825011  RAB3A; ras-related protein Rab-3A [KO:K07882]
106843180  CCK; cholecystokinin [KO:K05226]
106840443  CCKAR; cholecystokinin receptor type A [KO:K04194]
106827064  CHRM3; muscarinic acetylcholine receptor M3 isoform X1 [KO:K04131]
106829234  FFAR1; free fatty acid receptor 1 [KO:K04325]
106825688  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
106832309  GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
106823182  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:3.1.4.11]
106823191  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
106835172  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
106833627  PLCB3; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
106834634  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 isoform X1 [KO:K04960]
106834687  RYR2; ryanodine receptor 2 isoform X4 [KO:K04962]
106844236  VAMP2; vesicle-associated membrane protein 2 [KO:K13504]
106837103  STX1A; syntaxin-1A [KO:K04560]
106825827  SNAP25; synaptosomal-associated protein 25 isoform X1 [KO:K18211]
106835567  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
106823831  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
106840859  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
eai00020  Citrate cycle (TCA cycle)
eai04020  Calcium signaling pathway
KO pathway
ko04911   
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