KEGG   PATHWAY: shr04927
Entry
shr04927                    Pathway                                
Name
Cortisol synthesis and secretion - Sarcophilus harrisii (Tasmanian devil)
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
shr04927  Cortisol synthesis and secretion
shr04927

Other DBs
GO: 0043400
Organism
Sarcophilus harrisii (Tasmanian devil) [GN:shr]
Gene
100925922  POMC; pro-opiomelanocortin [KO:K05228]
100915134  MC2R; adrenocorticotropic hormone receptor [KO:K04200]
105749807  MRAP; melanocortin-2 receptor accessory protein [KO:K22398]
100930666  GNAS; guanine nucleotide-binding protein G(s) subunit alpha [KO:K04632]
100922193  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
100922434  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
100925657  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
100920243  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
100932634  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
100929278  ADCY7; adenylate cyclase type 7 isoform X3 [KO:K08047] [EC:4.6.1.1]
100923926  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
100926025  ADCY9; adenylate cyclase type 9 isoform X2 [KO:K08049] [EC:4.6.1.1]
100932935  PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B isoform X1 [KO:K18437] [EC:3.1.4.53]
100934646  PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A isoform X1 [KO:K18437] [EC:3.1.4.53]
100929360  cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
100915481  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
100934183  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X2 [KO:K04345] [EC:2.7.11.11]
100913731  cAMP-dependent protein kinase catalytic subunit alpha-like [KO:K04345] [EC:2.7.11.11]
100922802  NR0B1; nuclear receptor subfamily 0 group B member 1 [KO:K08562]
100920164  NR5A1; steroidogenic factor 1 [KO:K08560]
100931514  NR4A1; nuclear receptor subfamily 4 group A member 1 [KO:K04465]
100930024  SP1; transcription factor Sp1 isoform X1 [KO:K04684]
100928718  PBX1; pre-B-cell leukemia transcription factor 1 isoform X1 [KO:K09355]
100913327  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
100914193  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X3 [KO:K04450]
100913697  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
100926416  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
100913890  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
100916355  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
100917654  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
100923082  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
100922067  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
100932966  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
100930767  cytochrome P450 11B1, mitochondrial [KO:K00497] [EC:1.14.15.4]
100915970  steroid 17-alpha-hydroxylase/17,20 lyase isoform X1 [KO:K00512] [EC:1.14.14.19 1.14.14.32]
100913378  STAR; steroidogenic acute regulatory protein, mitochondrial [KO:K16931]
100929735  NCEH1; neutral cholesterol ester hydrolase 1 [KO:K14349] [EC:3.1.1.-]
100932795  AGT; angiotensinogen isoform X2 [KO:K09821]
100927259  AGTR1; type-1 angiotensin II receptor [KO:K04166]
100916183  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha isoform X1 [KO:K04634]
100920179  GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
100922938  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
100934049  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
100934311  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
100929015  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
100918532  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 isoform X7 [KO:K04958]
100921270  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
100916996  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 isoform X2 [KO:K04960]
100935232  KCNK2; potassium channel subfamily K member 2 isoform X1 [KO:K04913]
100921267  CACNA1G; voltage-dependent T-type calcium channel subunit alpha-1G isoform X1 [KO:K04854]
100934677  CACNA1H; voltage-dependent T-type calcium channel subunit alpha-1H isoform X1 [KO:K04855]
100916832  CACNA1I; voltage-dependent T-type calcium channel subunit alpha-1I [KO:K04856]
100926503  voltage-dependent L-type calcium channel subunit alpha-1C isoform X1 [KO:K04850]
100919750  CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D isoform X1 [KO:K04851]
100927554  CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F [KO:K04853]
100917433  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
111719559  ORAI1; calcium release-activated calcium channel protein 1 [KO:K16056]
100935331  KCNA4; potassium voltage-gated channel subfamily A member 4 [KO:K04877]
100934261  KCNK3; potassium channel subfamily K member 3 [KO:K04914]
100923750  LDLR; low-density lipoprotein receptor isoform X1 [KO:K12473]
100923937  SCARB1; scavenger receptor class B member 1 isoform X1 [KO:K13885]
100923284  cholesterol side-chain cleavage enzyme, mitochondrial [KO:K00498] [EC:1.14.15.6]
100913530  HSD3B2; 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 isoform X3 [KO:K00070] [EC:1.1.1.145 5.3.3.1]
100932451  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
shr00140  Steroid hormone biosynthesis
shr04020  Calcium signaling pathway
shr04024  cAMP signaling pathway
shr04960  Aldosterone-regulated sodium reabsorption
KO pathway
ko04927   
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