Angiotensin and Endothelin Receptor Structures With Implications for Signaling Regulation and Pharmacological Targeting

Abstract

In conjunction with the endothelin (ET) type A (ETAR) and type B (ETBR) receptors, angiotensin (AT) type 1 (AT1R) and type 2 (AT2R) receptors, are peptide-binding class A G-protein-coupled receptors (GPCRs) acting in a physiologically overlapping context. Angiotensin receptors (ATRs) are involved in regulating cell proliferation, as well as cardiovascular, renal, neurological, and endothelial functions. They are important therapeutic targets for several diseases or pathological conditions, such as hypertrophy, vascular inflammation, atherosclerosis, angiogenesis, and cancer. Endothelin receptors (ETRs) are expressed primarily in blood vessels, but also in the central nervous system or epithelial cells. They regulate blood pressure and cardiovascular homeostasis. Pathogenic conditions associated with ETR dysfunctions include cancer and pulmonary hypertension. While both receptor groups are activated by their respective peptide agonists, pathogenic autoantibodies (auto-Abs) can also activate the AT1R and ETAR accompanied by respective clinical conditions. To date, the exact mechanisms and differences in binding and receptor-activation mediated by auto-Abs as opposed to endogenous ligands are not well understood. Further, several questions regarding signaling regulation in these receptors remain open. In the last decade, several receptor structures in the apo- and ligand-bound states were determined with protein X-ray crystallography using conventional synchrotrons or X-ray Free-Electron Lasers (XFEL). These inactive and active complexes provide detailed information on ligand binding, signal induction or inhibition, as well as signal transduction, which is fundamental for understanding properties of different activity states. They are also supportive in the development of pharmacological strategies against dysfunctions at the receptors or in the associated signaling axis. Here, we summarize current structural information for the AT1R, AT2R, and ETBR to provide an improved molecular understanding.

Advances in the allostery of angiotensin II type 1 receptor

“…With the help of MD simulations, the four most reasonable mutual interfaces have been proposed: symmetric TM1,2,8, TM5, TM4, and TM4,5 [ 103 ]. The only report on AT1R homodimer structure (PDB ID: 6do1) indicates that the interface between individual protomers consists of hydrophobic and aromatic amino acid side chain contacts at ECL1, TM1, TM2, TM3, and H8 [ 104 ] (Fig. 4 E).…”

Insights into Endothelin Receptors in Pulmonary Hypertension

“…Ang II can stimulate the release of immunoreactive ET from rat vascular smooth muscle cells via the AT1 receptor. Moreover, it shares a common receptor–effector transduction pathway with ET, and the two may promote vascular smooth muscle cell growth through a common intracellular signaling mechanism [ 67 , 68 ]. Its activity is potentiated by growth factors such as PDGF, epidermal growth factor (EGF), basic FGF, TGF-α, TGF-β, and insulin-like growth factor to synergistically stimulate DNA synthesis in vascular smooth muscle cells, fibroblasts, mesangial cells, melanocytes, osteoblasts, and ECs [ 60 , 69 , 70 ].…”

Autoantibodies from patients with kidney allograft vasculopathy stimulate a proinflammatory switch in endothelial cells and monocytes mediated via GPCR-directed PAR1-TNF-α signaling

“…Here, anti-GPCR-directed RABs associated with allograft vasculopathy constitute a distinct phenotype of antibody-mediated rejection (ABMR) ( 9 , 10 ). After establishing the functional role of RABs directed against the angiotensin II type 1 receptor (AT1R) and endothelin receptor type A (ETAR) for vascular integrity and graft function/survival in the KTx setting ( 4 , 8 , 9 , 11 – 16 ), subsequent studies have identified several RABs directed against GPCR targets typically associated with the vasculature, such as protease-activated receptors (PARs), neuronal and chemokine receptors, and the levels of these RABs are often modulated with patient age and disease status ( 1 , 17 , 18 ). Vasculature-associated RAB targets can be found on different types of micro-/macro-vascular endothelial cells (ECs), vascular smooth muscle cells (VSCMs), and perivascular multipotent mesenchymal stromal/stem cells (MSCs), but also neuronal cells, which are all often employed as model systems to study respective molecular signaling mechanisms ( 1 , 19 , 20 ).…”