KEGG   PATHWAY: pon04927
Entry
pon04927                    Pathway                                
Name
Cortisol synthesis and secretion - Pongo abelii (Sumatran orangutan)
Description
Cortisol is the main endogenous glucocorticoid, which affects a plethora of physiological functions, e.g., lipid and glucose metabolism, metabolic homeostasis and adaptation to stress. Cortisol production is primarily regulated by corticotropin (ACTH) in zona fasciculata. The stimulatory effect of ACTH on cortisol synthesis depends on cAMP dependent signaling, but also involves membrane depolarization and increased cytosolic Ca2+. Each of cAMP and Ca2+ induces the expression of StAR, stimulating intramitochondrial cholesterol transfer, as well as the steroidogenic enzymes in the pathway from cholesterol to cortisol (e.g., CHE, CYP17A1, CYP11B1).
Class
Organismal Systems; Endocrine system
Pathway map
pon04927  Cortisol synthesis and secretion
pon04927

Other DBs
GO: 0043400
Organism
Pongo abelii (Sumatran orangutan) [GN:pon]
Gene
100460464  POMC; pro-opiomelanocortin [KO:K05228]
100436726  MC2R; adrenocorticotropic hormone receptor [KO:K04200]
100436117  MRAP; melanocortin-2 receptor accessory protein [KO:K22398]
100442753  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X3 [KO:K04632]
103888841  neuroendocrine secretory protein 55 [KO:K04632]
100449504  ADCY1; adenylate cyclase type 1 isoform X1 [KO:K08041] [EC:4.6.1.1]
100445431  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
100431221  ADCY3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
100460806  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
100454138  ADCY5; adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:4.6.1.1]
100438178  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
100436577  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
100461383  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
103889530  ADCY9; adenylate cyclase type 9 isoform X1 [KO:K08049] [EC:4.6.1.1]
100449849  PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B isoform X6 [KO:K18437] [EC:3.1.4.53]
100456736  PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A isoform X1 [KO:K18437] [EC:3.1.4.53]
100174748  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform 2 [KO:K04345] [EC:2.7.11.11]
100431906  PRKACG; cAMP-dependent protein kinase catalytic subunit gamma isoform X1 [KO:K04345] [EC:2.7.11.11]
100437102  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
100446689  NR0B1; nuclear receptor subfamily 0 group B member 1 [KO:K08562]
100450504  NR5A1; steroidogenic factor 1 isoform X1 [KO:K08560]
100172457  NR4A1; nuclear receptor subfamily 4 group A member 1 [KO:K04465]
100440745  SP1; transcription factor Sp1 isoform X1 [KO:K04684]
100440755  PBX1; pre-B-cell leukemia transcription factor 1 isoform X1 [KO:K09355]
100294619  CREB1; cyclic AMP-responsive element-binding protein 1 [KO:K05870]
100450554  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
100462459  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
100431578  cyclic AMP-dependent transcription factor ATF-4-like [KO:K04374]
100432292  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X1 [KO:K09048]
100436186  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
100438869  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
100127093  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
100441756  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
100439720  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
100172895  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
100459910  cytochrome P450 11B1, mitochondrial isoform X1 [KO:K00497] [EC:1.14.15.4]
100439753  steroid 17-alpha-hydroxylase/17,20 lyase [KO:K00512] [EC:1.14.14.19 1.14.14.32]
100455906  STAR; steroidogenic acute regulatory protein, mitochondrial [KO:K16931]
100172976  NCEH1; neutral cholesterol ester hydrolase 1 [KO:K14349] [EC:3.1.1.-]
100458106  AGT; angiotensinogen [KO:K09821]
100461588  AGTR1; type-1 angiotensin II receptor [KO:K04166]
100458686  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
100460338  GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
100458716  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
100460060  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11]
100434502  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
100461961  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
100445922  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 isoform X1 [KO:K04958]
100434318  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 isoform X1 [KO:K04959]
100434127  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
100435329  KCNK2; potassium channel subfamily K member 2 [KO:K04913]
100457657  CACNA1G; voltage-dependent T-type calcium channel subunit alpha-1G [KO:K04854]
100451537  CACNA1H; voltage-dependent T-type calcium channel subunit alpha-1H [KO:K04855]
100432497  CACNA1I; voltage-dependent T-type calcium channel subunit alpha-1I isoform X1 [KO:K04856]
100442085  CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C isoform X1 [KO:K04850]
100453904  CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D isoform X1 [KO:K04851]
100431752  CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853]
100433948  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
100432306  ORAI1; calcium release-activated calcium channel protein 1 [KO:K16056]
100171748  KCNA4; potassium voltage-gated channel subfamily A member 4 [KO:K04877]
100449819  KCNK3; potassium channel subfamily K member 3 [KO:K04914]
100447659  LDLR; low-density lipoprotein receptor isoform X1 [KO:K12473]
100459938  SCARB1; scavenger receptor class B member 1 isoform X1 [KO:K13885]
100433169  cholesterol side-chain cleavage enzyme, mitochondrial isoform X1 [KO:K00498] [EC:1.14.15.6]
100451655  3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 1 [KO:K00070] [EC:1.1.1.145 5.3.3.1]
100452394  3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 isoform X1 [KO:K00070] [EC:1.1.1.145 5.3.3.1]
100450898  LOW QUALITY PROTEIN: 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 1-like [KO:K00070] [EC:1.1.1.145 5.3.3.1]
100461354  steroid 21-hydroxylase isoform X1 [KO:K00513] [EC:1.14.14.16]
112131288  LOW QUALITY PROTEIN: steroid 21-hydroxylase-like [KO:K00513] [EC:1.14.14.16]
Compound
C00020  AMP
C00076  Calcium cation
C00187  Cholesterol
C00238  Potassium cation
C00410  Progesterone
C00575  3',5'-Cyclic AMP
C00735  Cortisol
C01176  17alpha-Hydroxyprogesterone
C01245  D-myo-Inositol 1,4,5-trisphosphate
C01953  Pregnenolone
C05138  17alpha-Hydroxypregnenolone
C05488  11-Deoxycortisol
Reference
PMID:24944026
  Authors
Gallo-Payet N, Battista MC
  Title
Steroidogenesis-adrenal cell signal transduction.
  Journal
Compr Physiol 4:889-964 (2014)
DOI:10.1002/cphy.c130050
Reference
PMID:15727807
  Authors
Enyeart JJ
  Title
Biochemical and Ionic signaling mechanisms for ACTH-stimulated cortisol production.
  Journal
Vitam Horm 70:265-79 (2005)
DOI:10.1016/S0083-6729(05)70008-X
Reference
PMID:25339223
  Authors
Bandulik S, Tauber P, Lalli E, Barhanin J, Warth R
  Title
Two-pore domain potassium channels in the adrenal cortex.
  Journal
Pflugers Arch 467:1027-42 (2015)
DOI:10.1007/s00424-014-1628-6
Reference
PMID:17494631
  Authors
Liu H, Enyeart JA, Enyeart JJ
  Title
Angiotensin II inhibits native bTREK-1 K+ channels through a PLC-, kinase C-, and PIP2-independent pathway requiring ATP hydrolysis.
  Journal
Am J Physiol Cell Physiol 293:C682-95 (2007)
DOI:10.1152/ajpcell.00087.2007
Reference
PMID:15994319
  Authors
Enyeart JJ, Danthi SJ, Liu H, Enyeart JA
  Title
Angiotensin II inhibits bTREK-1 K+ channels in adrenocortical cells by separate Ca2+- and ATP hydrolysis-dependent mechanisms.
  Journal
J Biol Chem 280:30814-28 (2005)
DOI:10.1074/jbc.M504283200
Reference
PMID:27242666
  Authors
Shen WJ, Azhar S, Kraemer FB
  Title
ACTH Regulation of Adrenal SR-B1.
  Journal
Front Endocrinol (Lausanne) 7:42 (2016)
DOI:10.3389/fendo.2016.00042
Reference
PMID:27065945
  Authors
Ruggiero C, Lalli E
  Title
Impact of ACTH Signaling on Transcriptional Regulation of Steroidogenic Genes.
  Journal
Front Endocrinol (Lausanne) 7:24 (2016)
DOI:10.3389/fendo.2016.00024
Reference
PMID:25905342
  Authors
Margioris AN, Tsatsanis C
  Title
ACTH Action on the Adrenals
  Journal
Endotext (2000)
Reference
PMID:25662280
  Authors
Spiga F, Lightman SL
  Title
Dynamics of adrenal glucocorticoid steroidogenesis in health and disease.
  Journal
Mol Cell Endocrinol 408:227-34 (2015)
DOI:10.1016/j.mce.2015.02.005
Reference
PMID:21962440
  Authors
Tsai LC, Beavo JA
  Title
The roles of cyclic nucleotide phosphodiesterases (PDEs) in steroidogenesis.
  Journal
Curr Opin Pharmacol 11:670-5 (2011)
DOI:10.1016/j.coph.2011.09.003
Reference
PMID:26807866
  Authors
Odermatt A, Strajhar P, Engeli RT
  Title
Disruption of steroidogenesis: Cell models for mechanistic investigations and as screening tools.
  Journal
J Steroid Biochem Mol Biol 158:9-21 (2016)
DOI:10.1016/j.jsbmb.2016.01.009
Reference
PMID:26271515
  Authors
Manna PR, Stetson CL, Slominski AT, Pruitt K
  Title
Role of the steroidogenic acute regulatory protein in health and disease.
  Journal
Endocrine 51:7-21 (2016)
DOI:10.1007/s12020-015-0715-6
Reference
PMID:26113808
  Authors
Jackson DS, Ramachandrappa S, Clark AJ, Chan LF
  Title
Melanocortin receptor accessory proteins in adrenal disease and obesity.
  Journal
Front Neurosci 9:213 (2015)
DOI:10.3389/fnins.2015.00213
Reference
PMID:23410915
  Authors
Cerda-Reverter JM, Agulleiro MJ, Cortes R, Sanchez E, Guillot R, Leal E, Fernandez-Duran B, Puchol S, Eley M
  Title
Involvement of melanocortin receptor accessory proteins (MRAPs) in the function of melanocortin receptors.
  Journal
Gen Comp Endocrinol 188:133-6 (2013)
DOI:10.1016/j.ygcen.2013.01.017
Reference
PMID:23858003
  Authors
Enyeart JJ, Enyeart JA
  Title
Ca2+ and K+ channels of normal human adrenal zona fasciculata cells: properties and modulation by ACTH and AngII.
  Journal
J Gen Physiol 142:137-55 (2013)
DOI:10.1085/jgp.201310964
Reference
PMID:27524977
  Authors
Midzak A, Papadopoulos V
  Title
Adrenal Mitochondria and Steroidogenesis: From Individual Proteins to Functional Protein Assemblies.
  Journal
Front Endocrinol (Lausanne) 7:106 (2016)
DOI:10.3389/fendo.2016.00106
Reference
PMID:26139209
  Authors
Calebiro D, Di Dalmazi G, Bathon K, Ronchi CL, Beuschlein F
  Title
cAMP signaling in cortisol-producing adrenal adenoma.
  Journal
Eur J Endocrinol 173:M99-106 (2015)
DOI:10.1530/EJE-15-0353
Reference
PMID:26038201
  Authors
Turcu AF, Auchus RJ
  Title
Adrenal steroidogenesis and congenital adrenal hyperplasia.
  Journal
Endocrinol Metab Clin North Am 44:275-96 (2015)
DOI:10.1016/j.ecl.2015.02.002
Related
pathway
pon00140  Steroid hormone biosynthesis
pon04020  Calcium signaling pathway
pon04024  cAMP signaling pathway
pon04960  Aldosterone-regulated sodium reabsorption
KO pathway
ko04927   
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