Development - EDNRB signaling

EDNRB signaling

Endothelin receptor type B (EDNRB) belongs to the guanine nucleotide binding protein (G-protein) coupled receptor family. Endothelin-1 is most investigated physiological ligand of EDNRB [1]. EDNRB binds to many types of the G-proteins but the main physiological consequence is exerted via its binding to the G-protein alpha-q/11 and G-protein alpha-i family subunits [2], [3], [4].

Scaffolding Caveolin 1, caveolae protein, 22kDa (Caveolin-1) interacts with EDNRB. EDNRB bound to Caveolin-1 is targeted to caveolae. Upon Endothelin-1 stimulation, EDNRB dissociates from Caveolin-1 and exits from the caveolae. Caveolae localization of EDNRB is one of the mechanisms to ensure the balance of EDNRB-mediated signal transduction [5].

ENDRB stimulation by Endothelin-1 (and, possibly, Endothelin-3) significantly enhances activity of Nitric oxide synthase 3 (eNOS) which catalyzes Nitric Oxide synthesis from L-arginine [6], [7]. The mechanism of Nitric Oxide production in this case includes the following steps. Endothelin-stimulated ENDRB activates G-protein beta/gamma dissociation from complex with G-protein alpha-i family. G-protein beta/gamma activates Phosphatidylinositol 3 kinase (PI3K) (most probably, Phosphoinositide-3-kinase, regulatory subunit 5 (PI3K reg class IB (p101)) and Phosphoinositide-3-kinase, catalytic, gamma polypeptide (PI3K cat class IB (p110-gamma)), which products of PtdIns(3,4,5)P3 from PtdIns(4,5)P2. PtdIns(4,5)P2, in turn, recruits v-akt murine thymoma viral oncogene homolog 1 (AKT(PKB)), which activates eNOS by phosphorylation and thus enhances Nitric Oxide production. Enhanced Nitric oxide production during EDNRB stimulation results in smooth muscle and vascular relaxation [7]. Nitric Oxide, in turn, enhances intracellular concentration of cGMP, most likely by activation of the Guanylate cyclase 1, soluble [6], [8]. Guanylate cyclase 1, soluble activity, in turn, can stimulate cGMP- dependent Protein kinase G, which abrogates downstream Mitogen activate protein kinases 1 and 3 (ERK1/2) phosphorylation by unknown mechanism [8].

Endothelin-1 via EDNRB induces activation of the downstream MAP kinases, mainly ERK1/2. The exact mechanism which leads to ERK1/2 activation is unclear but probably involves several pathways [9].

The first pathway proceeds via activation of the EDNRB by its ligands, leading to transformation of the G-protein alpha-q/11 which activates Phospholipase C beta (PLC beta) and leads to hydrolysis of Phosphatidylinositol 4,5-bisphosphate (Ptdins(4,5)P2) and production of Diacylglycerol (DAG) and Inositol trisphosphate (IP3) [10]. IP3 leads to Ca('2+) cytosol mobilization. Ca('2+) cytosol and DAG can activate some RAP1A, member of RAS oncogene family (RAP-1A) activating factor (e.g., RAS guanyl releasing protein 2 (CALDAG-GEFI)) which transform RAP-1A to active form. RAP-1A, in turn, activates effector - the v-raf murine sarcoma viral oncogene homolog B1 (B-Raf) [9]. DAG, probably, activates Protein kinase C epsilon (PKC-epsilon)/ v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras)/ v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1) pathway [9], [11].

The second pathway involves G-proteins alpha-i family [12] and, possibly, G-proteins beta/gamma [13], which activate cellular oncogene c-Src, which activates protein adaptor Shc/ Growth factor receptor bound 2 (GRB2)/ Son of sevenless homolog (SOS)/ H-Ras/ c-Raf-1 pathway [12], [14].

Both pathways are merged downstream of B-Raf and c-Raf-1. B-Raf and/or c-Raf-1 phosphorylate and activate Mitogen-activated protein kinase kinases 1 and 2 (MEK1(MAP2K1) and MEK2(MAP2K2)), which phosphorylate its main downstream effectors ERK1/2 [9].

ERK1/2 may induce activation of the Ribosomal protein S6 kinase 90kDa polypeptide 2 and 3 (p90RSK2 and p90RSK3). Most probably, ERK1/2 activation results in phosphorylation of the ELK1, member of ETS oncogene family (Elk-1). In turn, p90RSKs activation results in phosphorylation of cAMP responsive element binding protein 1 (CREB1) and Activating transcription factor 1 (ATF-1). Transcriptional activity of the Elk-1, ATF-1 and CREB1 in this case may induce cellular oncogene v-fos FBJ murine osteosarcoma viral oncogene homolog (c-Fos) expression [9].

Proliferation, cell migration and contraction is a physiological consequences of the ERK1/2 stimulation [15], [16], [17].

References:

1. Davenport AP
   International Union of Pharmacology. XXIX. Update on endothelin receptor nomenclature. Pharmacological reviews 2002 Jun;54(2):219-26
2. Takigawa M, Sakurai T, Kasuya Y, Abe Y, Masaki T, Goto K
   Molecular identification of guanine-nucleotide-binding regulatory proteins which couple to endothelin receptors. European journal of biochemistry / FEBS 1995 Feb 15;228(1):102-8
3. Shraga-Levine Z, Sokolovsky M
   Functional coupling of G proteins to endothelin receptors is ligand and receptor subtype specific. Cellular and molecular neurobiology 2000 Jun;20(3):305-17
4. Cramer H, Schmenger K, Heinrich K, Horstmeyer A, Boning H, Breit A, Piiper A, Lundstrom K, Muller-Esterl W, Schroeder C
   Coupling of endothelin receptors to the ERK/MAP kinase pathway. Roles of palmitoylation and G(alpha)q. European journal of biochemistry / FEBS 2001 Oct;268(20):5449-59
5. Yamaguchi T, Murata Y, Fujiyoshi Y, Doi T
   Regulated interaction of endothelin B receptor with caveolin-1. European journal of biochemistry / FEBS 2003 Apr;270(8):1816-27
6. McCormick J, Jain R
   Who actually has the "low health literacy"? Archives of internal medicine 2003 Jul 28;163(14):1745-6; author reply 1746
7. Liu S, Premont RT, Kontos CD, Huang J, Rockey DC
   Endothelin-1 activates endothelial cell nitric-oxide synthase via heterotrimeric G-protein betagamma subunit signaling to protein jinase B/Akt. The Journal of biological chemistry 2003 Dec 12;278(50):49929-35
8. Cheng TH, Shih NL, Chen SY, Lin JW, Chen YL, Chen CH, Lin H, Cheng CF, Chiu WT, Wang DL, Chen JJ
   Nitric oxide inhibits endothelin-1-induced cardiomyocyte hypertrophy through cGMP-mediated suppression of extracellular-signal regulated kinase phosphorylation. Molecular pharmacology 2005 Oct;68(4):1183-92
9. Schinelli S, Zanassi P, Paolillo M, Wang H, Feliciello A, Gallo V
   Stimulation of endothelin B receptors in astrocytes induces cAMP response element-binding protein phosphorylation and c-fos expression via multiple mitogen-activated protein kinase signaling pathways. The Journal of neuroscience : the official journal of the Society for Neuroscience 2001 Nov 15;21(22):8842-53
10. Kasuya Y, Abe Y, Hama H, Sakurai T, Asada S, Masaki T, Goto K
    Endothelin-1 activates mitogen-activated protein kinases through two independent signalling pathways in rat astrocytes. Biochemical and biophysical research communications 1994 Nov 15;204(3):1325-33
11. Li B, Kaetzel MA, Dedman JR
    Signaling pathways regulating murine cardiac CREB phosphorylation. Biochemical and biophysical research communications 2006 Nov 10;350(1):179-84
12. Lazarini F, Strosberg AD, Couraud PO, Cazaubon SM
    Coupling of ETB endothelin receptor to mitogen-activated protein kinase stimulation and DNA synthesis in primary cultures of rat astrocytes. Journal of neurochemistry 1996 Feb;66(2):459-65
13. Aquilla E, Whelchel A, Knot HJ, Nelson M, Posada J
    Activation of multiple mitogen-activated protein kinase signal transduction pathways by the endothelin B receptor requires the cytoplasmic tail. The Journal of biological chemistry 1996 Dec 6;271(49):31572-9
14. Vichi P, Whelchel A, Knot H, Nelson M, Kolch W, Posada J
    Endothelin-stimulated ERK activation in airway smooth-muscle cells requires calcium influx and Raf activation. American journal of respiratory cell and molecular biology 1999 Jan;20(1):99-105
15. Chakraborty C, Barbin YP, Chakrabarti S, Chidiac P, Dixon SJ, Lala PK
    Endothelin-1 promotes migration and induces elevation of [Ca2+]i and phosphorylation of MAP kinase of a human extravillous trophoblast cell line. Molecular and cellular endocrinology 2003 Mar 28;201(1-2):63-73
16. Shinohara H, Udagawa J, Morishita R, Ueda H, Otani H, Semba R, Kato K, Asano T
    Gi2 signaling enhances proliferation of neural progenitor cells in the developing brain. The Journal of biological chemistry 2004 Sep 24;279(39):41141-8
17. Luo G, Jamali R, Cao YX, Edvinsson L, Xu CB
    Vascular endothelin ET(B) receptor-mediated contraction requires phosphorylation of ERK1/2 proteins. European journal of pharmacology 2006 May 24;538(1-3):124-31