KEGG   PATHWAY: hsa04927
hsa04927                    Pathway                                
Cortisol synthesis and secretion - Homo sapiens (human)
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).
Organismal Systems; Endocrine system
Pathway map
hsa04927  Cortisol synthesis and secretion

nt06310  CRH-ACTH-cortisol signaling
nt06360  Cushing syndrome
N00297  ACTH-cortisol signaling pathway
N00306  SF-1-mediated transcription
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)
Other DBs
GO: 0043400
Homo sapiens (human) [GN:hsa]
5443  POMC; proopiomelanocortin [KO:K05228]
4158  MC2R; melanocortin 2 receptor [KO:K04200]
56246  MRAP; melanocortin 2 receptor accessory protein [KO:K22398]
2778  GNAS; GNAS complex locus [KO:K04632]
107  ADCY1; adenylate cyclase 1 [KO:K08041] [EC:]
108  ADCY2; adenylate cyclase 2 [KO:K08042] [EC:]
109  ADCY3; adenylate cyclase 3 [KO:K08043] [EC:]
196883  ADCY4; adenylate cyclase 4 [KO:K08044] [EC:]
111  ADCY5; adenylate cyclase 5 [KO:K08045] [EC:]
112  ADCY6; adenylate cyclase 6 [KO:K08046] [EC:]
113  ADCY7; adenylate cyclase 7 [KO:K08047] [EC:]
114  ADCY8; adenylate cyclase 8 [KO:K08048] [EC:]
115  ADCY9; adenylate cyclase 9 [KO:K08049] [EC:]
8622  PDE8B; phosphodiesterase 8B [KO:K18437] [EC:]
5151  PDE8A; phosphodiesterase 8A [KO:K18437] [EC:]
5566  PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:]
5567  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:]
5568  PRKACG; protein kinase cAMP-activated catalytic subunit gamma [KO:K04345] [EC:]
190  NR0B1; nuclear receptor subfamily 0 group B member 1 [KO:K08562]
2516  NR5A1; nuclear receptor subfamily 5 group A member 1 [KO:K08560]
3164  NR4A1; nuclear receptor subfamily 4 group A member 1 [KO:K04465]
6667  SP1; Sp1 transcription factor [KO:K04684]
5087  PBX1; PBX homeobox 1 [KO:K09355]
1385  CREB1; cAMP responsive element binding protein 1 [KO:K05870]
1386  ATF2; activating transcription factor 2 [KO:K04450]
468  ATF4; activating transcription factor 4 [KO:K04374]
10488  CREB3; cAMP responsive element binding protein 3 [KO:K09048]
90993  CREB3L1; cAMP responsive element binding protein 3 like 1 [KO:K09048]
64764  CREB3L2; cAMP responsive element binding protein 3 like 2 [KO:K09048]
84699  CREB3L3; cAMP responsive element binding protein 3 like 3 [KO:K09048]
148327  CREB3L4; cAMP responsive element binding protein 3 like 4 [KO:K09048]
9586  CREB5; cAMP responsive element binding protein 5 [KO:K09047]
1388  ATF6B; activating transcription factor 6 beta [KO:K09049]
1584  CYP11B1; cytochrome P450 family 11 subfamily B member 1 [KO:K00497] [EC:]
1586  CYP17A1; cytochrome P450 family 17 subfamily A member 1 [KO:K00512] [EC:]
6770  STAR; steroidogenic acute regulatory protein [KO:K16931]
57552  NCEH1; neutral cholesterol ester hydrolase 1 [KO:K14349] [EC:3.1.1.-]
183  AGT; angiotensinogen [KO:K09821]
185  AGTR1; angiotensin II receptor type 1 [KO:K04166]
2776  GNAQ; G protein subunit alpha q [KO:K04634]
2767  GNA11; G protein subunit alpha 11 [KO:K04635]
23236  PLCB1; phospholipase C beta 1 [KO:K05858] [EC:]
5330  PLCB2; phospholipase C beta 2 [KO:K05858] [EC:]
5331  PLCB3; phospholipase C beta 3 [KO:K05858] [EC:]
5332  PLCB4; phospholipase C beta 4 [KO:K05858] [EC:]
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]
3776  KCNK2; potassium two pore domain channel subfamily K member 2 [KO:K04913]
8913  CACNA1G; calcium voltage-gated channel subunit alpha1 G [KO:K04854]
8912  CACNA1H; calcium voltage-gated channel subunit alpha1 H [KO:K04855]
8911  CACNA1I; calcium voltage-gated channel subunit alpha1 I [KO:K04856]
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]
84876  ORAI1; ORAI calcium release-activated calcium modulator 1 [KO:K16056]
3739  KCNA4; potassium voltage-gated channel subfamily A member 4 [KO:K04877]
3777  KCNK3; potassium two pore domain channel subfamily K member 3 [KO:K04914]
3949  LDLR; low density lipoprotein receptor [KO:K12473]
949  SCARB1; scavenger receptor class B member 1 [KO:K13885]
1583  CYP11A1; cytochrome P450 family 11 subfamily A member 1 [KO:K00498] [EC:]
3283  HSD3B1; hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1 [KO:K00070] [EC:]
3284  HSD3B2; hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2 [KO:K00070] [EC:]
1589  CYP21A2; cytochrome P450 family 21 subfamily A member 2 [KO:K00513] [EC:]
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
Gallo-Payet N, Battista MC
Steroidogenesis-adrenal cell signal transduction.
Compr Physiol 4:889-964 (2014)
Enyeart JJ
Biochemical and Ionic signaling mechanisms for ACTH-stimulated cortisol production.
Vitam Horm 70:265-79 (2005)
Bandulik S, Tauber P, Lalli E, Barhanin J, Warth R
Two-pore domain potassium channels in the adrenal cortex.
Pflugers Arch 467:1027-42 (2015)
Liu H, Enyeart JA, Enyeart JJ
Angiotensin II inhibits native bTREK-1 K+ channels through a PLC-, kinase C-, and PIP2-independent pathway requiring ATP hydrolysis.
Am J Physiol Cell Physiol 293:C682-95 (2007)
Enyeart JJ, Danthi SJ, Liu H, Enyeart JA
Angiotensin II inhibits bTREK-1 K+ channels in adrenocortical cells by separate Ca2+- and ATP hydrolysis-dependent mechanisms.
J Biol Chem 280:30814-28 (2005)
Shen WJ, Azhar S, Kraemer FB
ACTH Regulation of Adrenal SR-B1.
Front Endocrinol (Lausanne) 7:42 (2016)
Ruggiero C, Lalli E
Impact of ACTH Signaling on Transcriptional Regulation of Steroidogenic Genes.
Front Endocrinol (Lausanne) 7:24 (2016)
Margioris AN, Tsatsanis C
ACTH Action on the Adrenals
Endotext (2000)
Spiga F, Lightman SL
Dynamics of adrenal glucocorticoid steroidogenesis in health and disease.
Mol Cell Endocrinol 408:227-34 (2015)
Tsai LC, Beavo JA
The roles of cyclic nucleotide phosphodiesterases (PDEs) in steroidogenesis.
Curr Opin Pharmacol 11:670-5 (2011)
Odermatt A, Strajhar P, Engeli RT
Disruption of steroidogenesis: Cell models for mechanistic investigations and as screening tools.
J Steroid Biochem Mol Biol 158:9-21 (2016)
Manna PR, Stetson CL, Slominski AT, Pruitt K
Role of the steroidogenic acute regulatory protein in health and disease.
Endocrine 51:7-21 (2016)
Jackson DS, Ramachandrappa S, Clark AJ, Chan LF
Melanocortin receptor accessory proteins in adrenal disease and obesity.
Front Neurosci 9:213 (2015)
Cerda-Reverter JM, Agulleiro MJ, Cortes R, Sanchez E, Guillot R, Leal E, Fernandez-Duran B, Puchol S, Eley M
Involvement of melanocortin receptor accessory proteins (MRAPs) in the function of melanocortin receptors.
Gen Comp Endocrinol 188:133-6 (2013)
Enyeart JJ, Enyeart JA
Ca2+ and K+ channels of normal human adrenal zona fasciculata cells: properties and modulation by ACTH and AngII.
J Gen Physiol 142:137-55 (2013)
Midzak A, Papadopoulos V
Adrenal Mitochondria and Steroidogenesis: From Individual Proteins to Functional Protein Assemblies.
Front Endocrinol (Lausanne) 7:106 (2016)
Calebiro D, Di Dalmazi G, Bathon K, Ronchi CL, Beuschlein F
cAMP signaling in cortisol-producing adrenal adenoma.
Eur J Endocrinol 173:M99-106 (2015)
Turcu AF, Auchus RJ
Adrenal steroidogenesis and congenital adrenal hyperplasia.
Endocrinol Metab Clin North Am 44:275-96 (2015)
hsa00140  Steroid hormone biosynthesis
hsa04020  Calcium signaling pathway
hsa04024  cAMP signaling pathway
hsa04960  Aldosterone-regulated sodium reabsorption
KO pathway

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