Biology Reference
In-Depth Information
5.2.
-Arrestins and other GPCRs in inflammation
5.2.1 Angiotensin II receptor type 1A
Angiotensin II is a potent vasopressor peptide hormone. In addition to its
role as an important effector controlling blood pressure, it binds its receptor,
the angiotensin II type 1A receptor (AGTR1, AT1R, or AT1AR), to medi-
ate the formation of reactive oxygen species and inflammatory responses. 83
For example, in liver, angiotensin II-dependent NF- k B activation leads to
proinflammatory cytokine release from hepatocytes and stellate cells that is
implicated in the development of hepatic fibrosis. 84 Studies suggested that
b -arrestins promote desensitization and sequestration of AGTR1. 85 Both
b -arrestin 1 and b -arrestin 2 showed similar roles in agonist-stimulated
receptor desensitization, while the b -arrestin 2 may have more profound
effects on angiotensin II-stimulated internalization of the AGTR1. 85
Furthermore, b -arrestin 2 also mediates chemotaxis through an AGTR1-
dependent and G protein-independent mechanism. 86
b
b -Arrestins also facil-
itate GPCR-mediated ERK activation but inhibit ERK-dependent
transcription by targeting activated ERK1/2 to nonnuclear substrates fol-
lowing angiotensin AT1A receptor stimulation. 87 Furthermore, b -arrestin
2 binds JNK and mediates ASK1 and MKK4 activity. 88
The angiotensin II receptor has been shown to play a role in immune-
mediated renal injury. 89,90 Deletion of AGTR1 in mice markedly attenu-
ated glomerular expression of CCL2 (MCP-1), proteinuria, and tissue
damage in an antiglomerular basement membrane nephritis model. 89
Angiotensin II binds its receptors on immune cells, triggering the prolifer-
ation of splenic lymphocytes and leading to the potency of cellular
alloimmune responses. 90 The absence of AGTR1 signaling accentuates
the immunosuppressive effects of the calcineurin inhibitor, cyclosporine. 90
The manipulation of b -arrestin-mediated renin-angiotensin signaling can
be used as a way to regulate immune responses.
5.2.2 b 2-Adrenergic receptor
b -Arrestin attenuates agonist-induced b 2AR signaling by GRK-mediated
desensitization 91 and by clathrin-mediated receptor internalization. 92 It is
reported that both isoforms of b -arrestins promote desensitization of
b 2ARs 85 ; however, deficiency in b -arrestin 2, not in b -arrestin 1, significantly
compromised the sequestration of b 2ARs. 85 A cAMP phosphodiesterase
PDE4 is recruited to the receptor- b -arrestin complex, and PDE4 plays a role
in the regulation of G protein switching by the b 2AR in cardiac myocytes. 93
Search WWH ::




Custom Search