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Lipid signaling:

Ceramide

  • Sphingomyelinase (SMase) or sphingomyelin phosphodiesterase is a hydrolase involved in sphingolipid metabolism. It catalyzes the breakdown of sphingomyelin (SM) to phosphocholine and ceramide[1].
  • Acid-beta-glucosidase or glucosylceramidase is a lysozomal enzyme (EC number 3.2.1.45), which cleaves glucosylceramide to glucose and ceramide. It catalyzes hydrolysis of the sphingolipid, , to at the acidic pH prevailing within the lysosome. .
  • The molecular function of galactosylceramidase is hydrolysis of a O-glycosyl bond to remove galactose from ceramide and other sphingolipids.

Sphingosine-1-Phosphate

Glucosylceramide

Phosphatidylinositol bisphosphate (PIP2)

Phosphatidylinositol 4,5-bisphosphate (PIP2) binds to and directly activates inwardly rectifying potassium channels. Inward rectifier KCh.

Prostaglandins

Endocannabinoids

Retinol derivatives

Retinal

Retinoic acid

Steroid Hormones and their receptors

This large and diverse class of steroids are biosynthesized from isoprenoids and structurally resemble cholesterol. Mammalian steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestogens. Vitamin D derivatives are a sixth closely related hormone system with homologous receptors. They have some of the characteristics of true steroids as receptor ligands. For example, is an important estrogen steroid hormone in both women and men. It is a typical steroid with core four-ring system (ABCD), composed of 17 carbon atoms.

Corticosteroids

Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involved in a wide range of physiological processes.

and its derivatives have some mineralocorticoid action in addition to the glucocorticoid effect.

(hydrocortisone) is a corticosteroid with both glucocorticoid and mineralocorticoid activity and effects.

Glucocorticoids

Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor. is a glucocorticoid medication. It is the most potent glucocorticoid and it has not mineralocorticoid potency.

  • Glucocorticoid receptor. (1m2z).
  • Forkhead box proteins (FOX) are transcription factors involved in regulation of gene expression.[3]. FOXO1 activation contributes to glucocorticoid-induced beta cell death[4]. FOX contain a DNA-binding motif (DBD) of 80-100 amino acids having a winged-helix shape.
    • .
    • . Water molecules shown as red spheres.
    • .
  • Nuclear receptor coactivator (NCOA) is a protein recruited by nuclear receptors in order to enhance or repress DNA transcription. NCOA is involved in coactivation with transcription factors[5]. NCOA1 shows histone acetyltransferase activity and is required for steroid hormone response. NCOA2 is a DNA transcription coactivator with glucocorticoid receptor.
    • .
    • .
    • . Water molecules are shown as red spheres.
    • .
    • .
  • Thioredoxin Reductase (TrxR) is an enzyme which reduces thioredoxin using NADPH[6]. Mutations in TrxR-2 are associated with familial glucocorticoid deficiency[7]. Thioredoxin Reductase (TrxR) is an enzyme which reduces thioredoxin using NADPH[8]. TrxR-2 is mitochondrial. For more details see User:Sarah Abdalla/Thioredoxin Reductase. TrxR and Trx form an [9]. . Water molecules are shown as red spheres.
  • Microsomal Prostaglandin E synthase (PGES) converts cyclooxygenase (COX)-derived prostaglandin to PGE2. It is membrane-associated and belongs to the microsomal glutathione S-transferase family. PGES is preferentially linked with the inducible COX-2[10] . PGES is induced by proinflammatory stimuli and down-regulated by anti-inflammatory glucocorticoids[11]. Microsomal Prostaglandin E synthase (coordinates are from OPM database. The [12]. Water molecules are shown as red spheres.

Mineralocorticoids

Mineralocorticoids are a class of corticosteroids. Mineralocorticoids are produced in the adrenal cortex and influence salt and water balances (electrolyte balance and fluid balance). The primary mineralocorticoid is .

  • Mineralocorticoid receptor (MR) in epithelial cells is activated by the mineralocorticoid hormone aldosterone promoting renal sodium retention and potassium excretion. It is nuclear receptor. In non epithelial cells MR is activated by cortisol[13]. MR is exposed to many steroids including cortisol, cortisone and progesterone, however, aldosterone and deoxycorticosterone are its physiological ligands. MR mutations are the principal cause of renal pseudohypoaldosteronism[14]. MR mutation S810L causes early-onset hypertension[15]. Inhibition of cardia MR prevents doxorubicin-induced cardiotoxicity[16]. MR is an important proadipogenic transcription factor that may mediate aldosterone and glucocorticoid effects on adipose tissue development and hence on obesity and development of metabolic syndrome[17]. The MR ligand aldosterone binds in a (Alpha Helices, Beta Strands , Loops ,Turns). [18]. . Water molecules are shown as red spheres.

Signaling Pathways:

ABA Signaling Pathway

Protein Kinases:

Tyrosine kinase

  • Receptor tyrosine kinases
  • Tyrosine kinase
  • Janus kinase or tyrosine-protein kinase JAK (JAK) are nonreceptor tyrosine kinases which transduces cytokine-mediated signals via the JAK-STAT pathway. The JAK-STAT pathway transmits signals through the cell membrane to DNA promoters thus causing transcription.

Protein kinase C

MAPK

CAMP-dependent protein kinase

Chemotaxis:

Mechanotransduction:

Thermoception

Transient receptor potential channels

Voltage-gated channels

Visual phototransduction

Light is detected by rhodopsin in rod and cone cells.

Photoreceptor pigments

Circadian clock

Protein phosphatases:

Second messengers

cAMP is second messenger

CAMP-dependent protein kinase

IP3 is second messenger

Receptors that activate this pathway (Phospholipase C) are mainly G protein-coupled receptors coupled to the Gαq subunit, including:

  • 5-HT2 serotonergic receptors (5-hydroxytryptamine receptor#Structural highlights/Specific Function of 5-HT2B).
  • α1 adrenergic receptors
  • Calcitonin receptors
  • Histamine H1 receptor. The H1 receptor is a histamine receptor belonging to the family of rhodopsin-like G-protein-coupled receptors. The H1 receptor is linked to an intracellular G-protein (Gq) that activates phospholipase C and the inositol triphosphate signaling pathway. When a ligand binds to a G protein-coupled receptor that is coupled to a Gq heterotrimeric G protein, the α-subunit of Gq can bind to and induce activity in the PLC isozyme PLC-β, which results in the cleavage of PIP2 into IP3 and DAG.
  • Metabotropic glutamate receptor 1 and metabotropic glutamate receptor 5 belong to group I and activate phospholipase C. For details see Metabotropic glutamate receptor 5.
  • M1, M3, and M5 muscarinic receptors. Muscarinic acetylcholine receptors (mAChR) contain 5 subtypes M1-M5. Subtypes M1, M3, M5 activate phospholipase C which leads to activation of protein kinase C.
  • Inositol 1,4,5-Trisphosphate Receptor

Paracrine signaling: fibroblast growth factor (FGF) family, Hedgehog family, Wnt family, and TGF-β superfamily

Fibroblast growth factor and Fibroblast growth factor receptor (FGFR). FGFR belongs to Receptor tyrosine kinases, class V.

Sonic Hedgehog

Ca2+ signalling processes

H+/K+-ATPase signal pathway (acetylcholine, histamine, and gastrin) activates the pump in order to move the vesicles toward the lumen.

Proton pump

Signal transducing adaptor proteins (STAPs)

GTPase

The Mitogen-activated protein kinase cascade

MAPKs are involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammatory cytokines. They regulate cell functions including proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis.

Inflammatory response

Allostery

ATPase


Nicotinic Acetylcholine Receptor, PDB code 2bg9

Drag the structure with the mouse to rotate

ReferencesReferences

  1. Chatterjee S. Neutral sphingomyelinase: past, present and future. Chem Phys Lipids. 1999 Nov;102(1-2):79-96. PMID:11001563
  2. Barna TM, Khan H, Bruce NC, Barsukov I, Scrutton NS, Moody PC. Crystal structure of pentaerythritol tetranitrate reductase: "flipped" binding geometries for steroid substrates in different redox states of the enzyme. J Mol Biol. 2001 Jul 6;310(2):433-47. PMID:11428899 doi:10.1006/jmbi.2001.4779
  3. Tuteja G, Kaestner KH. SnapShot: forkhead transcription factors I. Cell. 2007 Sep 21;130(6):1160. PMID:17889656 doi:http://dx.doi.org/10.1016/j.cell.2007.09.005
  4. Kaiser G, Gerst F, Michael D, Berchtold S, Friedrich B, Strutz-Seebohm N, Lang F, Haring HU, Ullrich S. Regulation of forkhead box O1 (FOXO1) by protein kinase B and glucocorticoids: different mechanisms of induction of beta cell death in vitro. Diabetologia. 2013 Jul;56(7):1587-95. doi: 10.1007/s00125-013-2863-7. Epub 2013, Feb 23. PMID:23435785 doi:http://dx.doi.org/10.1007/s00125-013-2863-7
  5. Horwitz KB, Jackson TA, Bain DL, Richer JK, Takimoto GS, Tung L. Nuclear receptor coactivators and corepressors. Mol Endocrinol. 1996 Oct;10(10):1167-77. PMID:9121485 doi:http://dx.doi.org/10.1210/mend.10.10.9121485
  6. Arner ES, Holmgren A. Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem. 2000 Oct;267(20):6102-9. PMID:11012661
  7. Prasad R, Chan LF, Hughes CR, Kaski JP, Kowalczyk JC, Savage MO, Peters CJ, Nathwani N, Clark AJ, Storr HL, Metherell LA. Thioredoxin Reductase 2 (TXNRD2) mutation associated with familial glucocorticoid deficiency (FGD). J Clin Endocrinol Metab. 2014 Aug;99(8):E1556-63. doi: 10.1210/jc.2013-3844. Epub, 2014 Mar 6. PMID:24601690 doi:http://dx.doi.org/10.1210/jc.2013-3844
  8. Arner ES, Holmgren A. Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem. 2000 Oct;267(20):6102-9. PMID:11012661
  9. Fritz-Wolf K, Kehr S, Stumpf M, Rahlfs S, Becker K. Crystal structure of the human thioredoxin reductase-thioredoxin complex. Nat Commun. 2011 Jul 12;2:383. doi: 10.1038/ncomms1382. PMID:21750537 doi:10.1038/ncomms1382
  10. Murakami M, Nakatani Y, Tanioka T, Kudo I. Prostaglandin E synthase. Prostaglandins Other Lipid Mediat. 2002 Aug;68-69:383-99. PMID:12432931
  11. Kudo I, Murakami M. Prostaglandin E synthase, a terminal enzyme for prostaglandin E2 biosynthesis. J Biochem Mol Biol. 2005 Nov 30;38(6):633-8. PMID:16336776
  12. Luz JG, Antonysamy S, Kuklish SL, Condon B, Lee MR, Allison D, Yu XP, Chandrasekhar S, Backer R, Zhang A, Russell M, Chang SS, Harvey A, Sloan AV, Fisher MJ. Crystal Structures of mPGES-1 Inhibitor Complexes Form a Basis for the Rational Design of Potent Analgesic and Anti-Inflammatory Therapeutics. J Med Chem. 2015 May 20. PMID:25961169 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b00330
  13. Frey FJ, Odermatt A, Frey BM. Glucocorticoid-mediated mineralocorticoid receptor activation and hypertension. Curr Opin Nephrol Hypertens. 2004 Jul;13(4):451-8. PMID:15199296
  14. Pujo L, Fagart J, Gary F, Papadimitriou DT, Claes A, Jeunemaitre X, Zennaro MC. Mineralocorticoid receptor mutations are the principal cause of renal type 1 pseudohypoaldosteronism. Hum Mutat. 2007 Jan;28(1):33-40. PMID:16972228 doi:10.1002/humu.20371
  15. Geller DS, Farhi A, Pinkerton N, Fradley M, Moritz M, Spitzer A, Meinke G, Tsai FT, Sigler PB, Lifton RP. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science. 2000 Jul 7;289(5476):119-23. PMID:10884226
  16. Lother A, Bergemann S, Kowalski J, Huck M, Gilsbach R, Bode C, Hein L. Inhibition of the cardiac myocyte mineralocorticoid receptor ameliorates doxorubicin-induced cardiotoxicity. Cardiovasc Res. 2018 Feb 1;114(2):282-290. doi: 10.1093/cvr/cvx078. PMID:28430882 doi:http://dx.doi.org/10.1093/cvr/cvx078
  17. Caprio M, Feve B, Claes A, Viengchareun S, Lombes M, Zennaro MC. Pivotal role of the mineralocorticoid receptor in corticosteroid-induced adipogenesis. FASEB J. 2007 Jul;21(9):2185-94. doi: 10.1096/fj.06-7970com. Epub 2007 Mar 23. PMID:17384139 doi:http://dx.doi.org/10.1096/fj.06-7970com
  18. Bledsoe RK, Madauss KP, Holt JA, Apolito CJ, Lambert MH, Pearce KH, Stanley TB, Stewart EL, Trump RP, Willson TM, Williams SP. A ligand-mediated hydrogen bond network required for the activation of the mineralocorticoid receptor. J Biol Chem. 2005 Sep 2;280(35):31283-93. Epub 2005 Jun 20. PMID:15967794 doi:http://dx.doi.org/10.1074/jbc.M504098200

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Alexander Berchansky