Angiotensin signaling via Beta-arrestin
Angiotensin II, a major effector peptide of the
renin-angiotensin system, is now believed to play a critical role in the pathogenesis of
cardiovascular remodeling associated with hypertension, heart failure, and
atherosclerosis [1].
Angiotensin II receptor type-1 mediates the major
cardiovascular effects of Angiotensin-II. It relate to
Guanine nucleotide-binding regulatory protein (G-protein)-coupled receptor (GPCR)
superfamily. [2] Human Angiotensin II receptor
type-1 is found in liver, lung, adrenal, and adrenocortical adenomas, but
not in pheochromocytomas [3].
In general, mechanisms used by GPCRs to stimulate Mitogen-activated protein kinases
(MAPKs) fall into one of several broad categories. GPCR signal transduction via
Beta-arrestins is among recently recognized signaling
mechanisms [4].
Upon binding with Angiotensin II,
Angiotensin II receptor type-1 is stabilized in its active
conformation and stimulates heterotrimeric G proteins dissotiation into alpha
(G-protein alpha q/11) and beta/gamma
(G-protein beta/gamma) subunits [5]. Only G-protein beta/gamma takes part
in Beta-arrestin-dependent activation of MAPKs.
G-protein beta/gamma subunits, along with
Phosphatidylinositol 4,5-biphosphate (PtdIns(4,5)P2),
facilitate translocation of G-protein-coupled receptor kinases 2 and 3
(GRK2 and GRK3) to the plasma
membrane, where these GRKs phosphorylate the activated
Angiotensin II receptor type1. Phospholipid-bound
GRK5 and GRK6 undergo
autophosphorylation, which is required for receptor kinase activity. Then,
GRK5 and GRK6 phosphorylate the
activated Angiotensin II receptor type-1 independently of
G-protein beta/gamma [6].
GRK2, GRK5 and
GRK6 are inhibited by Ca('2+)/Calmodulin
[6], [7]. The receptor-kinase activity of
GRK2 is enhanced if GRK2 is
phosphorylated by Protein kinase C conventional type (cPKC),
whereas receptor-kinase activity of GRK5 is diminished if
the GRK5 is phosphorylated by cPKC
[6].
Beta-arrestins are bound with agonist-stimulated and
GRKs-phosphorylated receptors only [8].
In addition, PKC phosphorylation sites have been mapped
to serine/threonine-rich regions in the COOH terminus of Angiotensin II
receptor type-1, which do not appear to be involved in
Beta-arrestin binding [7].
It has been clearly shown that internalization of the receptor and
Angiotensin II receptor type-1-mediated activation of
mitogen-activated protein kinase may be closely connected with
Beta-arrestin. In the case of GPCRs that bind tightly to
Beta-arrestin (such as the Angiotensin II
receptor type-1), multiprotein complex containing receptor,
Beta-arrestin, and activated MAPK internalize as a unit. It
results in accumulation of Mitogen-activated protein kinases 3, 1 and 10
(ERK1, ERK2 and
JNK3) and in endosomal vesicles [9], [10].
Agonist stimulation of Angiotensin II receptor type-1
promotes recruitment of a ternary complex containing V-src sarcoma viral oncogene homolog
(c-Src), Clathrin-associated protein complex (AP-2) and
Beta-arrestin. c-Src binds to
Beta-arrestin and an element of the AP-2 - beta 1 subunit of
Adapter-related protein complex 2 (Beta-adaptin 2). It would
stabilize the endocytic complex and allow the receptor to be efficiently targeted to the
Clathrin-coated pit (CCP) [11].
In addition, sustained Beta-arrestin ubiquitination is
required for its cotrafficking with activated receptor and for the generation of stable
compartmentalized ERK signals on endosomes. Activation of
Angiotensin II receptor type-1 by Angiotensin
II significantly increases binding of
Beta-arrestin2 and Mdm2 p53 binding protein homolog
(MDM2). It effectively shifts the equilibrium of
MDM2 subcellular distribution from nucleus to plasma
membrane. Functional consequences of the enhanced
Beta-arrestin2/MDM2 interaction
promote ubiquitination of Beta-arrestin2 and assist
internalization of Angiotensin II receptor type-1 [12].
Beta-arrestin recruits components of MAP kinase modules
to the agonist-receptor complex at a step prior to, or coincident with, receptor
internalization.
MAP kinase modules involve:
1) Proto-oncogen serine/threonine-protein kinase
(c-Raf-1), dual specificity Mitogen-activated protein kinase
kinase 1 (MEK1), ERK1
and ERK2 [10].
2) Apoptosis signal regulating kinase (ASK1),
Mitogen-activated protein kinase kinase 4 (MAP2K4),
JNK3 [9].
There are two isoforms of Beta-arrestin, termed
Beta-arrestin1 and
Beta-arrestin2. Link between
Beta-arrestin isoforms and Angiotensin II
receptor type-1-mediated activation of the MAPK cascade remains unclear.
Physiological levels of Beta-arrestin1 may act as
"dominant-negative" inhibitors of Angiotensin II receptor
type-1-Beta-arrestin2-mediated
ERK activation [13]. It has been shown that
Beta-arrestin1 participates in internalization of the GPCR
and binds to some elements of GPCR-mediated activation of MAPK [14], [15], [16].
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