KEGG   PATHWAY: pcad04927
Entry
pcad04927                   Pathway                                
Name
Cortisol synthesis and secretion - Physeter catodon (sperm whale)
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
pcad04927  Cortisol synthesis and secretion
pcad04927

Other DBs
GO: 0043400
Organism
Physeter catodon (sperm whale) [GN:pcad]
Gene
102991057  POMC; pro-opiomelanocortin [KO:K05228]
102996884  MC2R; adrenocorticotropic hormone receptor [KO:K04200]
102977203  MRAP; melanocortin-2 receptor accessory protein [KO:K22398]
102993267  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoform X2 [KO:K04632]
102987258  neuroendocrine secretory protein 55-like [KO:K04632]
102988341  LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(s) subunit alpha-like [KO:K04632]
102981199  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
102991224  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
102989136  ADCY3; adenylate cyclase type 3 isoform X3 [KO:K08043] [EC:4.6.1.1]
102985820  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
102983319  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
102986152  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
102985075  ADCY7; adenylate cyclase type 7 isoform X4 [KO:K08047] [EC:4.6.1.1]
102975211  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
102995803  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
102979718  PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B isoform X1 [KO:K18437] [EC:3.1.4.53]
102991676  PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A isoform X1 [KO:K18437] [EC:3.1.4.53]
112062704  LOW QUALITY PROTEIN: high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A-like [KO:K18437] [EC:3.1.4.53]
102981091  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
102995361  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
102989172  NR0B1; nuclear receptor subfamily 0 group B member 1 [KO:K08562]
102989112  NR5A1; steroidogenic factor 1 [KO:K08560]
102993259  NR4A1; nuclear receptor subfamily 4 group A member 1 [KO:K04465]
102973166  SP1; transcription factor Sp1 isoform X1 [KO:K04684]
102983198  PBX1; pre-B-cell leukemia transcription factor 1 isoform X2 [KO:K09355]
102989082  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
102974369  ATF2; LOW QUALITY PROTEIN: cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
102986837  LOW QUALITY PROTEIN: cyclic AMP-dependent transcription factor ATF-2-like [KO:K04450]
102984157  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
102994621  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X2 [KO:K09048]
102986078  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X3 [KO:K09048]
102987194  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
102975387  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
129391322  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
102985635  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X3 [KO:K09047]
102978131  ATF6B; LOW QUALITY PROTEIN: cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
102988484  cytochrome P450 11B1, mitochondrial [KO:K00497] [EC:1.14.15.4]
102989171  steroid 17-alpha-hydroxylase/17,20 lyase [KO:K00512] [EC:1.14.14.19 1.14.14.32]
102994328  STAR; steroidogenic acute regulatory protein, mitochondrial isoform X1 [KO:K16931]
102976073  NCEH1; neutral cholesterol ester hydrolase 1 [KO:K14349] [EC:3.1.1.-]
102991481  AGT; angiotensinogen [KO:K09821]
102980831  AGTR1; type-1 angiotensin II receptor [KO:K04166]
102979158  guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
102995887  GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
102995357  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X2 [KO:K05858] [EC:3.1.4.11]
102985636  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
102974165  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
102983015  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
102984842  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 isoform X1 [KO:K04959]
102992034  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 isoform X1 [KO:K04960]
102981407  KCNK2; potassium channel subfamily K member 2 [KO:K04913]
102996804  CACNA1G; voltage-dependent T-type calcium channel subunit alpha-1G isoform X1 [KO:K04854]
102984905  CACNA1H; voltage-dependent T-type calcium channel subunit alpha-1H isoform X1 [KO:K04855]
102986791  CACNA1I; voltage-dependent T-type calcium channel subunit alpha-1I [KO:K04856]
102989784  CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C isoform X1 [KO:K04850]
102976068  CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D isoform X1 [KO:K04851]
102992313  CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853]
102987099  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S isoform X10 [KO:K04857]
102975350  ORAI1; calcium release-activated calcium channel protein 1 [KO:K16056]
102994836  KCNA4; potassium voltage-gated channel subfamily A member 4 [KO:K04877]
102994612  KCNK3; potassium channel subfamily K member 3 [KO:K04914]
102984457  LDLR; low-density lipoprotein receptor isoform X1 [KO:K12473]
102990434  SCARB1; scavenger receptor class B member 1 isoform X4 [KO:K13885]
102978389  cholesterol side-chain cleavage enzyme, mitochondrial [KO:K00498] [EC:1.14.15.6]
102987751  3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase [KO:K00070] [EC:1.1.1.145 5.3.3.1]
102985160  steroid 21-hydroxylase [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
pcad00140  Steroid hormone biosynthesis
pcad04020  Calcium signaling pathway
pcad04024  cAMP signaling pathway
pcad04960  Aldosterone-regulated sodium reabsorption
KO pathway
ko04927   
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