KEGG   PATHWAY: oas04927
Entry
oas04927                    Pathway                                
Name
Cortisol synthesis and secretion - Ovis aries (sheep)
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
oas04927  Cortisol synthesis and secretion
oas04927

Other DBs
GO: 0043400
Organism
Ovis aries (sheep) [GN:oas]
Gene
443212  POMC; pro-opiomelanocortin precursor [KO:K05228]
443482  MC2R; adrenocorticotropic hormone receptor [KO:K04200]
105609272  MRAP; melanocortin-2 receptor accessory protein isoform X2 [KO:K22398]
101115640  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoforms short isoform X5 [KO:K04632]
101102411  neuroendocrine secretory protein 55 [KO:K04632]
101117327  ADCY1; adenylate cyclase type 1 isoform X1 [KO:K08041] [EC:4.6.1.1]
101102089  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
101108203  ADCY3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
101119139  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
105602258  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
101105735  ADCY6; adenylate cyclase type 6 isoform X2 [KO:K08046] [EC:4.6.1.1]
101112667  ADCY7; adenylate cyclase type 7 isoform X7 [KO:K08047] [EC:4.6.1.1]
101121944  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
101122401  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
101105363  PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A isoform X3 [KO:K18437] [EC:3.1.4.53]
101107286  PDE8B; LOW QUALITY PROTEIN: high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B [KO:K18437] [EC:3.1.4.53]
443094  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
101108785  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
101113131  NR0B1; nuclear receptor subfamily 0 group B member 1 [KO:K08562]
443464  NR5A1; steroidogenic factor 1 [KO:K08560]
101113222  NR4A1; nuclear receptor subfamily 4immunitygroup A member 1 isoform X1 [KO:K04465]
101104139  SP1; transcription factor Sp1 isoform X1 [KO:K04684]
101108880  PBX1; pre-B-cell leukemia transcription factor 1 isoform X1 [KO:K09355]
443118  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
101108548  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
100216465  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
101107485  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X2 [KO:K09048]
101114243  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
101108743  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
101113586  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
101113882  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
101112976  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X2 [KO:K09047]
101113631  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X2 [KO:K09049]
767576  CYP11B1; cytochrome P450 11B1, mitochondrial precursor [KO:K00497] [EC:1.14.15.4]
101102377  cytochrome P450 11B1, mitochondrial isoform X4 [KO:K00497] [EC:1.14.15.4]
105601846  CYP17; steroid 17-alpha-hydroxylase/17,20 lyase [KO:K00512] [EC:1.14.14.19 1.14.14.32]
493968  CYP17A1; steroid 17-alpha-hydroxylase/17,20 lyase precursor [KO:K00512] [EC:1.14.14.19 1.14.14.32]
443122  STAR; steroidogenic acute regulatory protein, mitochondrial precursor [KO:K16931]
101113553  NCEH1; neutral cholesterol ester hydrolase 1 isoform X1 [KO:K14349] [EC:3.1.1.-]
101119440  AGT; angiotensinogen [KO:K09821]
443107  AGTR1; type-1 angiotensin II receptor [KO:K04166]
101112295  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
101119215  GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
101103585  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
101113074  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
101116105  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
101106864  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X9 [KO:K05858] [EC:3.1.4.11]
101108864  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 isoform X4 [KO:K04958]
101113317  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 isoform X2 [KO:K04959]
114109674  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 isoform X2 [KO:K04960]
101111729  KCNK2; potassium channel subfamily K member 2 isoform X1 [KO:K04913]
101117004  CACNA1G; voltage-dependent T-type calcium channel subunit alpha-1G isoform X2 [KO:K04854]
101119120  CACNA1H; voltage-dependent T-type calcium channel subunit alpha-1H isoform X1 [KO:K04855]
101123461  CACNA1I; voltage-dependent T-type calcium channel subunit alpha-1I [KO:K04856]
101116562  CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C isoform X6 [KO:K04850]
101106371  CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D isoform X9 [KO:K04851]
101104552  CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853]
101108767  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S isoform X1 [KO:K04857]
101102013  calcium release-activated calcium channel protein 1 [KO:K16056]
101118217  KCNA4; potassium voltage-gated channel subfamily A member 4 [KO:K04877]
100141302  KCNK3; potassium channel subfamily K member 3 [KO:K04914]
443535  LDLR; low-density lipoprotein receptor isoform X2 [KO:K12473]
101115654  SCARB1; scavenger receptor class B member 1 isoform X5 [KO:K13885]
100048994  CYP11A1; cholesterol side-chain cleavage enzyme, mitochondrial precursor [KO:K00498] [EC:1.14.15.6]
100190978  HSD3B1; 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 1 [KO:K00070] [EC:1.1.1.145 5.3.3.1]
105612707  steroid 21-hydroxylase isoform X1 [KO:K00513] [EC:1.14.14.16]
114108679  steroid 21-hydroxylase isoform X1 [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
oas00140  Steroid hormone biosynthesis
oas04020  Calcium signaling pathway
oas04024  cAMP signaling pathway
oas04960  Aldosterone-regulated sodium reabsorption
KO pathway
ko04927   
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