KEGG   PATHWAY: hsa04927
Entry
hsa04927                    Pathway                                
Name
Cortisol synthesis and secretion - Homo sapiens (human)
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
hsa04927  Cortisol synthesis and secretion
hsa04927

Network
nt06310  CRH-ACTH-cortisol signaling
nt06360  Cushing syndrome
  Element
N00297  ACTH-cortisol signaling pathway
N00306  SF-1-mediated transcription
Drug
D00146  Corticotropin (USP/INN)
D00284  Cosyntropin (USP)
D02105  Tetracosactide acetate (JAN)
D03593  Corticotropin zinc hydroxide
D05827  Seractide acetate (USAN)
D06544  Corticotropin, repository (USP)
D07417  Alsactide (INN)
D09801  Giractide acetate (JAN)
D09937  Giractide (INN)
D10950  Levoketoconazole (USAN/INN)
D13102  Atumelnant (USAN/INN)
D13103  Atumelnant maleate (USAN)
Other DBs
GO: 0043400
Organism
Homo sapiens (human) [GN:hsa]
Gene
10488  CREB3; cAMP responsive element binding protein 3 [KO:K09048]
107  ADCY1; adenylate cyclase 1 [KO:K08041] [EC:4.6.1.1]
108  ADCY2; adenylate cyclase 2 [KO:K08042] [EC:4.6.1.1]
109  ADCY3; adenylate cyclase 3 [KO:K08043] [EC:4.6.1.1]
111  ADCY5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
112  ADCY6; adenylate cyclase 6 [KO:K08046] [EC:4.6.1.1]
113  ADCY7; adenylate cyclase 7 [KO:K08047] [EC:4.6.1.1]
114  ADCY8; adenylate cyclase 8 [KO:K08048] [EC:4.6.1.1]
115  ADCY9; adenylate cyclase 9 [KO:K08049] [EC:4.6.1.1]
1385  CREB1; cAMP responsive element binding protein 1 [KO:K05870]
1386  ATF2; activating transcription factor 2 [KO:K04450]
1388  ATF6B; activating transcription factor 6 beta [KO:K09049]
148327  CREB3L4; cAMP responsive element binding protein 3 like 4 [KO:K09048]
1583  CYP11A1; cytochrome P450 family 11 subfamily A member 1 [KO:K00498] [EC:1.14.15.6]
1584  CYP11B1; cytochrome P450 family 11 subfamily B member 1 [KO:K00497] [EC:1.14.15.4]
1586  CYP17A1; cytochrome P450 family 17 subfamily A member 1 [KO:K00512] [EC:1.14.14.19 1.14.14.32]
1589  CYP21A2; cytochrome P450 family 21 subfamily A member 2 [KO:K00513] [EC:1.14.14.16]
183  AGT; angiotensinogen [KO:K09821]
185  AGTR1; angiotensin II receptor type 1 [KO:K04166]
190  NR0B1; nuclear receptor subfamily 0 group B member 1 [KO:K08562]
196883  ADCY4; adenylate cyclase 4 [KO:K08044] [EC:4.6.1.1]
23236  PLCB1; phospholipase C beta 1 [KO:K05858] [EC:3.1.4.11]
2516  NR5A1; nuclear receptor subfamily 5 group A member 1 [KO:K08560]
2767  GNA11; G protein subunit alpha 11 [KO:K04635]
2776  GNAQ; G protein subunit alpha q [KO:K04634]
2778  GNAS; GNAS complex locus [KO:K04632]
3164  NR4A1; nuclear receptor subfamily 4 group A member 1 [KO:K04465]
3283  HSD3B1; hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1 [KO:K00070] [EC:1.1.1.145 5.3.3.1]
3284  HSD3B2; hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2 [KO:K00070] [EC:1.1.1.145 5.3.3.1]
3708  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]
3709  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
3710  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
3739  KCNA4; potassium voltage-gated channel subfamily A member 4 [KO:K04877]
3776  KCNK2; potassium two pore domain channel subfamily K member 2 [KO:K04913]
3777  KCNK3; potassium two pore domain channel subfamily K member 3 [KO:K04914]
3949  LDLR; low density lipoprotein receptor [KO:K12473]
4158  MC2R; melanocortin 2 receptor [KO:K04200]
468  ATF4; activating transcription factor 4 [KO:K04374]
5087  PBX1; PBX homeobox 1 [KO:K09355]
5151  PDE8A; phosphodiesterase 8A [KO:K18437] [EC:3.1.4.53]
5330  PLCB2; phospholipase C beta 2 [KO:K05858] [EC:3.1.4.11]
5331  PLCB3; phospholipase C beta 3 [KO:K05858] [EC:3.1.4.11]
5332  PLCB4; phospholipase C beta 4 [KO:K05858] [EC:3.1.4.11]
5443  POMC; proopiomelanocortin [KO:K05228]
5566  PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
5567  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
5568  PRKACG; protein kinase cAMP-activated catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
56246  MRAP; melanocortin 2 receptor accessory protein [KO:K22398]
57552  NCEH1; neutral cholesterol ester hydrolase 1 [KO:K14349] [EC:3.1.1.-]
64764  CREB3L2; cAMP responsive element binding protein 3 like 2 [KO:K09048]
6667  SP1; Sp1 transcription factor [KO:K04684]
6770  STAR; steroidogenic acute regulatory protein [KO:K16931]
775  CACNA1C; calcium voltage-gated channel subunit alpha1 C [KO:K04850]
776  CACNA1D; calcium voltage-gated channel subunit alpha1 D [KO:K04851]
778  CACNA1F; calcium voltage-gated channel subunit alpha1 F [KO:K04853]
779  CACNA1S; calcium voltage-gated channel subunit alpha1 S [KO:K04857]
84699  CREB3L3; cAMP responsive element binding protein 3 like 3 [KO:K09048]
84876  ORAI1; ORAI calcium release-activated calcium modulator 1 [KO:K16056]
8622  PDE8B; phosphodiesterase 8B [KO:K18437] [EC:3.1.4.53]
8911  CACNA1I; calcium voltage-gated channel subunit alpha1 I [KO:K04856]
8912  CACNA1H; calcium voltage-gated channel subunit alpha1 H [KO:K04855]
8913  CACNA1G; calcium voltage-gated channel subunit alpha1 G [KO:K04854]
90993  CREB3L1; cAMP responsive element binding protein 3 like 1 [KO:K09048]
949  SCARB1; scavenger receptor class B member 1 [KO:K13885]
9586  CREB5; cAMP responsive element binding protein 5 [KO:K09047]
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
hsa00140  Steroid hormone biosynthesis
hsa04020  Calcium signaling pathway
hsa04024  cAMP signaling pathway
hsa04960  Aldosterone-regulated sodium reabsorption
KO pathway
ko04927   

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