Functional interactions between 7TM receptors in the Renin-Angiotensin System—Dimerization or crosstalk?

Abstract

Abstract:The Renin-Angiotensin System (RAS) is important for the regulation of cardiovascular physiology, where it controls blood pressure, and salt-and water homeostasis. Dysregulation of RAS can lead to severe diseases including hypertension, diabetic nephropathy, and cardiac arrhythmia, and -failure.The importance of the RAS is clearly emphasised by the widespread use of drugs targeting this system in clinical practice. These include, renin inhibitors, angiotensin II receptor type I blockers, and inhibitors of the angiotensin converting enzyme. Some of the important effectors within the system are 7 transmembrane (7TM) receptors (or G-protein-coupled receptors) such as the angiotensin II Receptors type I and II (AT1R and AT2R) and the MAS-oncogene receptor. Several findings indicate that the 7TM receptors can form both homo-and heterodimers, or higher orders of oligomers. Furthermore, dimerization may be important for receptor function, and in the development of cardiovascular diseases. This is very significant, since "dimers" may provide pharmacologists with novel targets for improved drug therapy. However, we know that 7TM receptors can mediate signals as monomeric units, and so far it has been very difficult to establish if our observations reflect actual well defined dimerization or merely reflect close proximity between the receptors and/or various types of functional interaction. In this review, we will present and critically discuss the current data on 7TM receptor dimerization with a clear focus on the RAS, and delineate future challenges within the field.

Expression and Distribution of NADPH Oxidase Isoforms in Human Myometrium—Role in Angiotensin II-induced Hypertrophy1

“…Homodimerization and heterodimerization in the AT1 and AT2 have been shown to modulate the effect of Ang II, perhaps in a tissue-specific manner [60,62]. We have observed a basal stimulation of 3 H-leucine incorporation of 18% by 10 lM AT1 antagonist losartan and a more profound stimulation of 32% by 10 lM AT2 antagonist PD123319.…”

“…Formation of homo-or hetero-oligomers is commonly found among G protein-coupled receptors and has complicated our understanding of the signaling networks [60]. It has been found that AT1-mediated signaling was activated and enhanced by heterodimerization with the bradykinin B 2 receptor [61].…”

Quantitative Phosphoproteomics Dissection of Seven-transmembrane Receptor Signaling Using Full and Biased Agonists

“…Furthermore, phosphorylation independent of G␣ q protein activation was also seen on three previously undiscovered FGF receptor phosphorylation sites. Ang II also resulted in phosphorylation of other 7TMRs including the ␤ 2 -adrenergic receptor, which is an AT 1 R interaction partner on a functional level (45).…”

Role of Mas receptor antagonist (A779) in renal hemodynamics in condition of blocked angiotensin II receptors in rats

“…When Ang 1-7 and A779 were used at equimolar doses, Ang 1-7 antagonist failed to block Ang 1-7-induced depressor response against AT1R blockade; suggesting that Ang 1-7 may act via the AT2R (43). Therefore, there is a complex interaction between RAS receptors (4, 6), and some actions of Ang 1-7 may also be blocked by AT1R (1,5) or AT2R antagonists (9); suggesting a crosstalk between the MasR and Ang II receptors (20). Other data indicated that the antidiuretic effect of AVE0991 that mimics the effects of Ang 1-7 was completely blocked by PD123319 and partially blocked by losartan (43).…”

“…The role of Ang 1-7 in cardiovascular system has been studied; however, the exact mechanism is not completely understood (17). In addition, blockade of AT1R and AT2R also inhibits some actions of Ang 1-7, which indicates a crosstalk between MasR and Ang II receptors (4,6,20,45). Moreover, increase in nitric oxide (NO), bradykinin, and prostacyclin production complicates the mechanism of Ang 1-7 action (3).…”