Targeting the Angiotensin II Type 1 Receptor in Cerebrovascular Diseases: Biased Signaling Raises New Hopes

Figures

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  Figure 1. Implication of AT1 in cerebrovascular diseases. ACE: angiotensin-converting enzyme; Ang II: angiotensin II; AT1: angiotensin II type 1 receptor; mRNA: messenger ribonucleic acid; ROS: reactive oxygen species. The figure was prepared using the Servier Medical Art website (Creative Commons Attribution 3.0 unported License).

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  Figure 2. Chemical structures of the main angiotensin receptor blockers (ARB) used in therapeutics. The biphenyltetrazole (or the bioisosteric biphenyl carboxylic acid for telmisartan) is highlighted in blue.

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  Figure 3. Overview of the cellular signaling pathways activated by AT1 after stimulation of the renin–angiotensin system (RAS). AA: arachidonic acid; ACE: angiotensin-converting enzyme; ACE2: angiotensin-converting enzyme 2; AKT: protein kinase B; Ang-(1–7): angiotensin (1–7); Ang I: angiotensin I; Ang II: angiotensin II; ARHGEF1: Rho guanine nucleotide exchange factor 1. AT1: angiotensin II type 1 receptor; AT2: angiotensin II type 2 receptor; ARBs: angiotensin receptor blockers; CaM: calmodulin; DAG: diacylglycerol; ER: endoplasmic reticulum; ERK1/2: extracellular signal regulated kinase ½; GRK: G protein-coupled receptor kinase; GSNO: S-nitrosoglutathione; IP3: inositol triphosphate; JAK2: Janus kinase 2; JNK: c-Jun N-terminal Kinase; MAPK: mitogen-activated protein kinases; MasR: Mas receptor; MLC: myosin light chain; MLCK: myosin light chain kinase; MLCP: myosin light chain phosphatase; mTOR: mammalian target of rapamycin; MYPT: myosin phosphatase target subunit; NFκB: nuclear factor kappa B; NOX: NADPH oxidase; PA: phosphatidic acid; PC: phosphatidylcholine; PI3K: phosphoinositide 3 kinase; PIP2: phosphatidylinositol-4, 5-diphosphate; PLA2: phospholipase A2; PLCβ: phospholipase Cβ;…

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  Figure 4. Superimposition of the three known structures of AT1. Inactive (salmon), canonical active (green) and alternative active (cyan). TM6 and TM7 are located in the front. In the inactive structure, TM6 is remarkably bent inside the receptor, while TM7 is slightly twisted outside. The reference inactive structure of AT1 has been chosen as PDB code 4YAY (from [99]). Canonical active and alternative active structures have been chosen as PDB code 6OS0 and 6OS1 respectively (from [96]). The figure was prepared with the PyMOL software (The PyMOL Molecular Graphics System, Version 2.5.0. Schrödinger, LLC).

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  Figure 5. Illustration of the long range allosteric network of AT1 inducing its switch to canonical active conformation. (a): Top view of the canonical (green) and alternative (cyan) active conformations of AT1. (b): Superimposition of the intracellular part of AT1 in its canonical (green) and alternative (cyan) active conformations. Canonical active and alternative active structures are simulation data available in supplementary material from [98]. The figure was prepared with the PyMOL software (The PyMOL Molecular Graphics System, Version 2.5.0. Schrödinger, LLC).

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  Figure 6. β-arrestin biased agonists of AT1 favor its alternative active conformation. (a): Comparison of the amino acid sequences of angiotensin II (Ang II) and of the main β-arrestin biased agonists of AT1; Ang II: angiotensin II; SII: [Sar1,Ile4,Ile8] angiotensin II peptide analog; TRV023 and TRV027: β-arrestin biased AT1 agonists. (b): Superimposition of the structure of AT1 bound to Ang II (green, PDB code 6OS0; Ang II appears in orange) or to the β-arrestin biased agonist TRV023 (cyan, PDB code 6OS1; TRV023 appears in purple). The phenyl group of the C-terminal part of Ang II (highlighted in blue) goes deep into the ligand pocket, inducing a rotation of L1123.36 and of N1113.35 (yellow arrows). It yields the canonical structure of AT1 (appears in green). The C-terminal part of TRV023 comprises a less bulky alanine residue (highlighted in grey) which does not induce such motion, yielding the alternative structure (in cyan). This panel was prepared with the PyMOL software (The PyMOL Molecular Graphics System, Version 2.5.0. Schrödinger, LLC).

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  Figure 7. Positions of the cysteine 289 residue in the three known AT1 structures. Superimposition of the three known AT1 structures: inactive (salmon), canonical active (green) and alternative active (cyan). TM6 and TM7 are located in the front. C289 residue is indicated by arrows. The reference inactive structure of AT1 has been chosen as PDB code 4YAY (from Zhang et al. [99]). Canonical active and alternative active structures are simulation data available in supplementary material from Suomivuori et al. [98]. The figure was prepared with the PyMOL software (The PyMOL Molecular Graphics System, Version 2.5.0. Schrödinger, LLC).