Angiotensin receptors: Introduction
General
The classification of the angiotensin receptors is based on the sequence of genes, structural features of the encoded proteins and their pharmacological properties (i.e. ligand-binding affinities and functional efficacies for selective agonists and antagonists), including the signal transduction mechanisms. Two types of mammalian receptors for the major renin-angiotensin receptor hormone angiotensinII (Ang II) have been cloned [28,43,54-55] and are designated by the abbreviations AT1 for angiotensin type 1 receptor and AT2 for angiotensin type 2 receptor [8,15]. The human genome contains single genes for AT1 and AT2. In rodents and zebra fish two genes encoding subtypes AT1a and AT1b exist [22,41,70]. Previous suggestion for a distinct Ang III(angiotensin 2-8) receptor, i.e. AT3 [40] or MAS [35] receptor has disappeared. The AT2 receptor mediated effects in various tissues indeed may critically require local conversion of Ang II to Ang III through the involvement of resident aminopeptidase in specific tissues such as kidney and brain [30,45,60]. The mammalian receptor for the Ang IV(angiotensin 3-8), named AT4 has been cloned and broadly characterized [2,10,34,37]. The AT4 receptor is insulin-regulated membrane aminopeptidase and a selective receptor for Ang IV. In addition, the receptor postulated for angiotensin 1-7 [42], has been tentatively assigned as the GPCR encoded by MAS oncogene [64]. The existence of other receptor types, which are neither AT1 nor AT2, has been proposed on pharmacological grounds but has not been unequivocally proven. In addition, a cytosolic binding protein and a nuclear receptor have been reported but are still poorly characterized [74,77]. A membrane-bound metalloendopeptidase, neurolysin (EC 3.4.24.16) was identified as the novel non-AT1, non-AT2 Ang II binding protein in rodent and human brain membranes [75,83].
Most of the conventional actions of Ang II, such as maintainance of blood pressure and glomerular filtration rate in response to extracellular volume depletion are mediated through the AT1receptor. Consequently, significantly greater advances have been made in developing pharmacological agents targeting the AT1 receptor compared to the others. Although Ang II has been viewed as a blood-borne hormone produced in the circulation, it is now established that in many tissues such as the brain, kidney, heart, and blood vessels, Ang II is formed locally and functions as a paracrine and autocrine hormone [31].
Pharmacological characteristics
The AT1 and AT2 receptors are membrane glycoproteins, members of the seven transmembrane-domain (7TM), G protein-coupled receptor superfamily [16,31-32]. Pharmacologically, the typical features of AT1 receptors are their selective affinity for biphenylimidazoles (typified by losartan) and their insensitivity to tetrahydroimidazopyridines (such as PD123177). The AT1 receptor is inactivated upon treatment with thiol reagents. By contrast, the AT2 receptor has low affinity for losartan and high affinity for PD123177 and a peptide derivative, CGP42112 (Figures 1, 2). The AT2 receptor is activated when treated with thiol reagents [24]. Although the sequence homology between the AT1 and AT2 receptors is only 30%, the natural ligand angiotensin II and peptide antagonists such as [Sar1, Ile8] Ang II do not distinguish between the two receptors. The MAS receptor is not pharmacologically related to AT1 and AT2 receptors.
The AT1 Receptor
In humans, the gene encoding the AT1 receptor is located on chromosome 3. The AT1A and AT1B originate from two closely related, but distinct genes are located on chromosomes 17 and 2, respectively in rodents. AT1A and AT1B receptors differ in 19 amino acids, mainly in the C-terminal region. The rodent AT1A and AT1B receptors are pharmacologically indistinguishable and have identical functional properties. Expression of AT1A and AT1B receptor genes are, however, differentially regulated. The AT1 receptor is ubiquitously expressed, including vascular smooth muscle, liver, kidney, heart, lung, adrenal cortex, pituitary and brain. Mutations disrupting AT1 receptor functions are not known, however genetic variants of the AGTR1 gene resulting from single nucleotide polymorphisms in the non-coding regions are documented. Studies aimed at finding significant association of AGTR1 gene variants with human pathological conditions in different populations are currently underway.
The molecular mass of human AT1 receptor is ≈41kDa and contains three N-glycosylation sites, eight phosphorylation sites, and six cysteine residues. The three-dimensional structure of the AT1 receptor is maintained by two disulphide bridges [24,28,55,58]. High-affinity binding of Ang II is determined by specific amino acid residues located on or near the extracellular regions of the receptor, as well as by residues in the transmembrane domain. These residues are probably in close proximity in the native receptor and held together by interactions between 7TM helices, the inter helical loops and the disulphide bridges [3,24,26,58]. Experimentally mapped site for binding of non-peptide antagonists such as losartan, EXP3174, candesartan and olmesartan overlaps with the membrane embedded portion of the Ang II binding pocket involving TMIII-VII [3,26,53,58,65,76]. Specific residues in TMIII, TMV, TMVI and TMVII of the AT1 receptor directly interact with both peptide and non-peptide ligands accounting for direct competitive binding which is experimentally observed. A class of AT1 receptor selective insurmountable non-peptide antagonists reversibly interact with the same membrane embedded residues [76]. Agonist binding to the AT1 receptor is reduced by GTP, suggesting the existence of heterogeneous states of receptor affinity due to association with G proteins. Selective signalling analogues of Ang II, which activate G protein independent AT1 receptor functions with low or zero efficacy for G protein mediated functions are described, but their mechanism of AT1 receptor activation is yet to be fully elucidated [38,78,85].
Figure 1. AT1 receptor agonists and antagonists
Signal transduction
Agonist binding to the AT1 receptor leads to the recruitment of heterotrimeric G proteins (Gq/G11 and/or Gi/Go) and/or adaptor proteins such as β-arrestin, GIT1, CARMA and/or kinases such as JAK2, pp60-src, GRK2 [9,16,33]. The stimulation of multiple intracellular signalling pathways within a cell or different signalling events induced by Ang II in different tissues occur in multiple phases, in seconds, minutes or hours, and involve the selective activation of multiple pathways over time. Classically, the signal transduction mechanisms of the AT1 receptor depend on different effectors: phospholipase (PL) C (formation of Inositol(1,4,5)P3 and DAG); voltage-dependent Ca2+ channels; PLD (cleavage of phosphatidylcholine); PLA2 (formation of prostaglandins and prostanoids); and adenylate cyclase (decrease in cAMP production). Cell specific effects have been described. For instance, in smooth muscle and some epithelial cells Ang II, like many growth factors, promotes activation of tyrosine-kinases such as pp60src and the JAK--STAT pathway [33,66]. The β-arrestin2 recruited to the AT1 receptor mediates activation of Ser/Thr kinases such as mitogen-activated protein (MAP) kinase spatially restricted to the cytoplasmic compartment [12,78]. Adaptor proteins such as GIT1 and CARMA1 recruited by the AT1 receptor activate, respectively, big MAPK (ERK5) and NFkB. Long-term activation of the NADH-NADPH oxidase pathway has also been implicated in gene induction and cell growth.
The AT2 Receptor
The gene coding for the AT2 receptor is located on chromosome X [46]. Unlike the AT1 receptor, no additional types or splice variants of the AT2 receptor have been reported in either man or rodents. The AT2 receptor has a molecular mass of ≈41kDa. The receptor contains five N-glycosylation sites, five phosphorylation sites, and 14 cysteine residues [43,54]. The cysteine residues in the extracellular region of AT2 receptor form two disulphide bonds. Both affinity and avidity of the AT2 receptor for ligands increases when reducing agents break one of the two disulphide bonds [24,58]. There is also a lack of effect of GTP analogues upon ligand-binding to AT2 sites. Expression of the AT2 receptor is developmentally regulated: it is highly expressed in various foetal tissues and at a lower density in adult adrenal medulla, brain, and reproductive tissues [16,32]. It appears to be re-expressed or up-regulated after vascular injury, myocardial infarction, cardiac failure or wound healing, possibly reflecting re-activation of a foetal genetic programme [21,50,52,57]. Preclinical in vitro and in vivo studies indicated that the AT2 receptor counterbalances the effect of the AT1 receptor [50,52,57,72,80]. Recent studies using the novel AT2 receptor non-peptide agonist for intervention in spinal cord injuries demonstrate a potential role beyond blood pressure regulation [56]. Genetic variants of the AGTR2 gene resulting from single nucleotide polymorphisms in the non-coding regions are also known. Mutations disrupting AT2 receptor functions are reported for X-linked mental retardation and related disorders [5,51,82]. In general, reports of mutations in the AGTR2 locus are more than mutations in the AGTR1 locus.
Signal transduction
The signal transduction mechanism of the AT2 receptor is still poorly understood. Although the sequence mofifs such as 'DRY' and NPxxY involved in G protein-activation of GPCRs are retained, agonist stimulation of the AT2 receptor does not incude an increase in cAMP, InsP3 and DAG formation [20,84]. The AT2 receptor does not undergo agonist-induced receptor phosphorylation [25]. A Giα 2-3 protein susceptible to pertussis toxin has been reported to participate in the signal transduction mechanism of the AT2 receptor [36,89]. Depending on the tissues, activation of the AT2 receptor appears to stimulate intracellular mechanisms involving Tyr and Ser/Thr phosphatases such as MKP-1, SHP-1 and PP2A, leading to the inactivation of the AT1 receptor- and growth factor- activated kinases [6,17,23,39,59,69,88]. As a consequence, there is an inactivation of MAP kinase, antiproliferation, promotion of apoptosis, repolarization trough opening of delayed-rectifier K+ channels and calcium and voltage activated potassium channel, closing of T -type Ca2+ channels and vasodilation [4,7,13,19,27,44,67,86-88,90]. The phosphatase activity is controlled by a cellular redox mechanism [62,71] involving bradykinin, nitric oxide and cGMP formation [29,47,68,79]. Through its phosphatase activity, the AT2 receptor regulates the NFκB pathway [61,63] and interferes with the inflammatory process [86-87]. Experimental studies suggest a protective action of AT2 receptor in tissue repair and regeneration. the c-kit(+)AT2(+) progenitor cell population has been identified in rat heart and bone marrow, which increases after induction of myocardial infarction. The AT2 receptor mediates cardiac homing of the c-kit(+) progenitor cells and promote repair of infarct tissue. Several modalities can result in AT2 receptor stimulation. For instance, AT1 receptor blockers can directly increase more angiotensin available to AT2 receptor. The AT2 receptor is constitutively active, hence inhibition of AT1 receptor can indirectly unmask hidden effects of AT2 receptor is constitutive activity. When inducing cell differentiation, the AT2 receptor can also stimulate MAP kinases Erk1/Erk2 [73].
The AT4 Receptor
The AT4 receptor has been identified by molecular cloning, pharmacological characterization of cloned receptor. The AT4 receptor is a class II transmembrane protein which is also known as insulin regulated aminopeptidase (IRAP), and oxytocinase (OTase) [1,81]. Ang 3-8 (Ang IV) binds selectively, reversibly, saturably and with high affinity (Kd 1 nM) to the IRAP/AT4 receptor [14], which has very low affinity for Ang II and for the AT1 and AT2 receptor antagonists. This "receptor" is widely distributed in brain and peripheral organs such as heart, vessels, adrenals, kidney, colon and prostate [14] Stable synthetic analogues of Ang IV such as Norleucine 1-Ang IV and divalinal-Ang IV act as AT4 receptor agonist and antagonist ligands, respectively [14]. LVV-haemorphin is an endogenous ligand for the AT4 receptor [1]. Ang IV and LVV-haemorphin compete for the binding of 125I-Nle1-Ang IV in IRAP-transfected HEK293 cells with IC50 values in the nanomolar range [1]. In membranes from tissue, covalent binding studies on AT4 binding sites have consistently revealed the presence of a 165 kDa peptide similar to that of IRAP [1,81].
OTase/IRAP is a type II integral membrane protein, homologous to aminopeptidases A, N, and other Zn2+-dependent aminopeptidases. It has a short intracellular domain, a single transmembrane-spanning domain and a large extracellular domain containing the catalytic site. It colocalized with Glut-4 vesicles. Ang IV inhibits the activity of OTase/IRAP and thereby reduces the processing of other bioactive peptides such as oxytocin, metenkephalin, dynorphin, neuromedin.
The Zn-binding state of IRAP might be a key factor in function of the protein as aminopeptidase and/or a signal transducing receptor, the AT4 receptor. The Zn-bound and apo-forms of IRAP have distinct pharmacological profiles [18]. Knowledge of the AT4 receptor-signalling pathway is incomplete. The AT4 receptor does not seem to be coupled to a G protein [55]. Whether the AT4 binding domain functions as a receptor as well as an enzyme regulatory site has yet to be determined.
It is likely that Ang IV has a physiological role in various functions such as cognition, cardiovascular and renal metabolism, and also in pathological conditions such as diabetes and hypertension. Ang IV binding to the AT4 receptor may be promoting the release of vasodilators such as nitric oxide, causing collagen accumulation in hypertrophied heart, controlling sodium transport in the kidney [28]. Pharmacological studies link the IRAP/AT4 receptor to enhanced learning and memory in normal rodents and reversal of the memory deficits seen in animal models of amnesia and possible involvement in cognition. Through binding Ang IV and hemorphin IRAP/AT4 receptor may enhance spatial working memory through enhanced hippocampal glucose uptake or blood flow. Ang IV may act through the inhibition of the activity of IRAP to reduce the degradation of oxytocin at the spinal cord, thereby leading to anti-hyperalgesia. The antidepressant-like effect of oxytocin is absent in IRAP/AT4 receptor-null mice [11,48]. Functional interaction between AT4 and the adenosine receptors may be involved in generalized seizure generation [49]. In conclusion, the IRAP/AT4 receptor has many receptor-like qualities in terms of ligand affinity but also has many enzymatic characteristics.
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