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 . 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 , , .
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
ENDRB stimulation by
Endothelin-1 (and, possibly,
enhances activity of Nitric oxide synthase 3 (eNOS) which
catalyzes Nitric Oxide synthesis from
L-arginine , . 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(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 . Nitric
Oxide, in turn, enhances intracellular concentration of
cGMP, most likely by activation of the
Guanylate cyclase 1, soluble , . 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 .
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
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) . 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) . 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 , .
The second pathway involves G-proteins alpha-i family
 and, possibly, G-proteins
beta/gamma , which activate cellular oncogene
c-Src, which activates protein adaptor
Shc/ Growth factor receptor bound 2
(GRB2)/ Son of sevenless homolog
pathway , .
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 .
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)
Proliferation, cell migration and contraction is a physiological consequences of the
ERK1/2 stimulation , , .
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