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
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)
DBLINKS     GO: 0043400
ORGANISM    Homo sapiens (human) [GN:hsa]
GENE        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: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]
            196883  ADCY4; adenylate cyclase 4 [KO:K08044] [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]
            8622  PDE8B; phosphodiesterase 8B [KO:K18437] [EC:3.1.4.53]
            5151  PDE8A; phosphodiesterase 8A [KO:K18437] [EC:3.1.4.53]
            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]
            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: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]
            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:3.1.4.11]
            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]
            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:1.14.15.6]
            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]
            1589  CYP21A2; cytochrome P450 family 21 subfamily A member 2 [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
REL_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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