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].

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