KEGG   PATHWAY: lav04927
lav04927                    Pathway                                

Cortisol synthesis and secretion - Loxodonta africana (African savanna elephant)
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
lav04927  Cortisol synthesis and secretion

Other DBs
GO: 0043400
Loxodonta africana (African savanna elephant) [GN:lav]
100669102  POMC; LOW QUALITY PROTEIN: pro-opiomelanocortin [KO:K05228]
100667193  MC2R; adrenocorticotropic hormone receptor [KO:K04200]
100669277  MRAP; melanocortin-2 receptor accessory protein [KO:K22398]
100655206  guanine nucleotide-binding protein G(s) subunit alpha isoform X1 [KO:K04632]
100669226  neuroendocrine secretory protein 55-like [KO:K04632]
100671072  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:]
100673570  ADCY2; LOW QUALITY PROTEIN: adenylate cyclase type 2 [KO:K08042] [EC:]
100674724  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:]
100675525  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:]
100670244  ADCY5; LOW QUALITY PROTEIN: adenylate cyclase type 5 [KO:K08045] [EC:]
100653532  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:]
100653771  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:]
100661616  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:]
100663448  ADCY9; LOW QUALITY PROTEIN: adenylate cyclase type 9 [KO:K08049] [EC:]
100670699  PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B [KO:K18437] [EC:]
100658501  PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A isoform X3 [KO:K18437] [EC:]
100656966  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:]
100674245  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:]
100672848  NR0B1; LOW QUALITY PROTEIN: nuclear receptor subfamily 0 group B member 1 [KO:K08562]
100667099  NR5A1; steroidogenic factor 1 isoform X1 [KO:K08560]
100654848  NR4A1; nuclear receptor subfamily 4 group A member 1 [KO:K04465]
100662543  SP1; transcription factor Sp1 [KO:K04684]
100658312  PBX1; pre-B-cell leukemia transcription factor 1 isoform X1 [KO:K09355]
100675162  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
100657989  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
100662521  ATF4; cyclic AMP-dependent transcription factor ATF-4 isoform X2 [KO:K04374]
100653565  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
100673694  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
100666211  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
100670574  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
100677344  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
100675079  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
100666885  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X2 [KO:K09049]
100654178  cytochrome P450 11B2, mitochondrial-like [KO:K00497] [EC:]
100660963  steroid 17-alpha-hydroxylase/17,20 lyase [KO:K00512] [EC:]
100664947  STAR; steroidogenic acute regulatory protein, mitochondrial [KO:K16931]
100668092  NCEH1; neutral cholesterol ester hydrolase 1 isoform X1 [KO:K14349] [EC:3.1.1.-]
100670141  AGT; LOW QUALITY PROTEIN: angiotensinogen [KO:K09821]
100659079  AGTR1; type-1 angiotensin II receptor [KO:K04166]
100656672  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha isoform X1 [KO:K04634]
100675896  guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
100670617  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X3 [KO:K05858] [EC:]
100672435  PLCB1; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:]
100668575  PLCB2; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:]
100663829  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:]
100665028  ITPR1; LOW QUALITY PROTEIN: inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]
100667845  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
100659666  ITPR3; LOW QUALITY PROTEIN: inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
100654542  KCNK2; potassium channel subfamily K member 2 isoform X1 [KO:K04913]
100666554  CACNA1G; voltage-dependent T-type calcium channel subunit alpha-1G isoform X1 [KO:K04854]
100675598  CACNA1H; LOW QUALITY PROTEIN: voltage-dependent T-type calcium channel subunit alpha-1H [KO:K04855]
100660332  CACNA1I; LOW QUALITY PROTEIN: voltage-dependent T-type calcium channel subunit alpha-1I [KO:K04856]
100659992  CACNA1D; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851]
100674649  CACNA1F; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1F [KO:K04853]
100673089  CACNA1S; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
100669326  ORAI1; calcium release-activated calcium channel protein 1 [KO:K16056]
100667029  KCNA4; potassium voltage-gated channel subfamily A member 4 [KO:K04877]
100672525  KCNK3; potassium channel subfamily K member 3 [KO:K04914]
100669109  LDLR; low-density lipoprotein receptor isoform X2 [KO:K12473]
100660517  SCARB1; scavenger receptor class B member 1 [KO:K13885]
100665050  cholesterol side-chain cleavage enzyme, mitochondrial [KO:K00498] [EC:]
100659049  HSD3B2; LOW QUALITY PROTEIN: 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 [KO:K00070] [EC:]
100658069  LOW QUALITY PROTEIN: steroid 21-hydroxylase [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)
lav00140  Steroid hormone biosynthesis
lav04020  Calcium signaling pathway
lav04024  cAMP signaling pathway
lav04960  Aldosterone-regulated sodium reabsorption
KO pathway

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