KEGG   PATHWAY: lav04911
Entry
lav04911                    Pathway                                
Name
Insulin secretion - Loxodonta africana (African savanna elephant)
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
lav04911  Insulin secretion
lav04911

Other DBs
GO: 0030073
Organism
Loxodonta africana (African savanna elephant) [GN:lav]
Gene
100677089  SLC2A1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
100669209  SLC2A2; solute carrier family 2, facilitated glucose transporter member 2 [KO:K07593]
100658238  GCK; glucokinase [KO:K12407] [EC:2.7.1.2]
100671543  TRPM4; LOW QUALITY PROTEIN: transient receptor potential cation channel subfamily M member 4 [KO:K04979]
100668326  ATP1A3; LOW QUALITY PROTEIN: sodium/potassium-transporting ATPase subunit alpha-3 [KO:K01539] [EC:7.2.2.13]
100667801  sodium/potassium-transporting ATPase subunit alpha-4 [KO:K01539] [EC:7.2.2.13]
100674070  ATP1A2; sodium/potassium-transporting ATPase subunit alpha-2 [KO:K01539] [EC:7.2.2.13]
100661428  ATP1A1; sodium/potassium-transporting ATPase subunit alpha-1 [KO:K01539] [EC:7.2.2.13]
100655666  ATP1B3; sodium/potassium-transporting ATPase subunit beta-3 [KO:K01540]
100660792  ATP1B4; protein ATP1B4 isoform X2 [KO:K01540]
100676526  ATP1B1; sodium/potassium-transporting ATPase subunit beta-1 [KO:K01540]
100668753  ATP1B2; sodium/potassium-transporting ATPase subunit beta-2 [KO:K01540]
111752838  FXYD2; sodium/potassium-transporting ATPase subunit gamma [KO:K01538]
100660003  ABCC8; ATP-binding cassette sub-family C member 8 isoform X2 [KO:K05032]
100671185  KCNJ11; ATP-sensitive inward rectifier potassium channel 11 isoform X1 [KO:K05004]
100659992  CACNA1D; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851]
100674649  CACNA1F; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1F [KO:K04853]
100673089  CACNA1S; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
104846071  CAMK2A; calcium/calmodulin-dependent protein kinase type II subunit alpha [KO:K04515] [EC:2.7.11.17]
100653927  CAMK2G; calcium/calmodulin-dependent protein kinase type II subunit gamma isoform X1 [KO:K04515] [EC:2.7.11.17]
100663321  CAMK2D; calcium/calmodulin-dependent protein kinase type II subunit delta isoform X2 [KO:K04515] [EC:2.7.11.17]
100658516  CAMK2B; calcium/calmodulin-dependent protein kinase type II subunit beta [KO:K04515] [EC:2.7.11.17]
100656201  KCNMA1; calcium-activated potassium channel subunit alpha-1 isoform X6 [KO:K04936]
100675383  KCNU1; LOW QUALITY PROTEIN: potassium channel subfamily U member 1 [KO:K05274]
100663278  KCNMB1; calcium-activated potassium channel subunit beta-1 [KO:K04937]
100658510  KCNMB2; calcium-activated potassium channel subunit beta-2 [KO:K04938]
100657662  KCNMB3; calcium-activated potassium channel subunit beta-3 isoform X3 [KO:K04939]
100668504  KCNMB4; calcium-activated potassium channel subunit beta-4 [KO:K04941]
100673007  KCNN1; small conductance calcium-activated potassium channel protein 1 isoform X1 [KO:K04942]
100663280  small conductance calcium-activated potassium channel protein 2 isoform X1 [KO:K04943]
100677291  KCNN3; small conductance calcium-activated potassium channel protein 3 isoform X2 [KO:K04944]
100657419  KCNN4; intermediate conductance calcium-activated potassium channel protein 4 [KO:K04945]
100676198  GCG; glucagon [KO:K05259]
100674677  GLP1R; glucagon-like peptide 1 receptor [KO:K04581]
100672824  GIP; gastric inhibitory polypeptide [KO:K05258]
100654522  GPR119; glucose-dependent insulinotropic receptor [KO:K08424]
100662363  ADCYAP1; pituitary adenylate cyclase-activating polypeptide [KO:K05262]
100677150  ADCYAP1R1; pituitary adenylate cyclase-activating polypeptide type I receptor isoform X2 [KO:K04587]
100655206  guanine nucleotide-binding protein G(s) subunit alpha isoform X1 [KO:K04632]
100669226  neuroendocrine secretory protein 55-like [KO:K04632]
100671072  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
100673570  ADCY2; LOW QUALITY PROTEIN: adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
100674724  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
100675525  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
100670244  ADCY5; LOW QUALITY PROTEIN: adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
100653532  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
100653771  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
100661616  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
100663448  ADCY9; LOW QUALITY PROTEIN: adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
100656966  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
100674245  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
100675162  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
100657989  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
100662521  ATF4; cyclic AMP-dependent transcription factor ATF-4 isoform X2 [KO:K04374]
100653565  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
100673694  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
100666211  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
100670574  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
100677344  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
100675079  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
100666885  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X2 [KO:K09049]
100667513  PDX1; LOW QUALITY PROTEIN: pancreas/duodenum homeobox protein 1 [KO:K07594]
100661112  INS; insulin [KO:K04526]
100660747  RAPGEF4; rap guanine nucleotide exchange factor 4 [KO:K04351]
100653733  RIMS2; LOW QUALITY PROTEIN: regulating synaptic membrane exocytosis protein 2 [KO:K15297]
111749764  LOW QUALITY PROTEIN: protein piccolo-like [KO:K16882]
100664755  RAB3A; ras-related protein Rab-3A [KO:K07882]
100670232  CCK; cholecystokinin [KO:K05226]
100666827  CCKAR; cholecystokinin receptor type A [KO:K04194]
100667215  CHRM3; muscarinic acetylcholine receptor M3 [KO:K04131]
100671890  FFAR1; free fatty acid receptor 1 [KO:K04325]
100656672  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha isoform X1 [KO:K04634]
100675896  guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
100670617  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X3 [KO:K05858] [EC:3.1.4.11]
100672435  PLCB1; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
100668575  PLCB2; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
100663829  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11]
100659666  ITPR3; LOW QUALITY PROTEIN: inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
100676989  ryanodine receptor 2 [KO:K04962]
100672461  VAMP2; vesicle-associated membrane protein 2 isoform X1 [KO:K13504]
100676727  STX1A; LOW QUALITY PROTEIN: syntaxin-1A [KO:K04560]
100661719  SNAP25; synaptosomal-associated protein 25 isoform X1 [KO:K18211]
100665537  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
100672078  PRKCB; LOW QUALITY PROTEIN: protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
100671733  PRKCG; LOW QUALITY PROTEIN: 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
lav00020  Citrate cycle (TCA cycle)
lav04020  Calcium signaling pathway
KO pathway
ko04911   
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