Ferraino Krysten E, Cora Natalie, Pollard Celina M, Sizova Anastasiya, Maning Jennifer, Lymperopoulos Anastasios
Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA.
Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA.
Cell Signal. 2021 Jun;82:109967. doi: 10.1016/j.cellsig.2021.109967. Epub 2021 Feb 25.
Angiotensin II (AngII) uses two distinct G protein-coupled receptor (GPCR) types, ATR and ATR, to exert a plethora of physiologic effects in the body and to significantly affect cardiovascular homeostasis. Although not much is known about the signaling of the ATR, ATR signaling is known to be quite pleiotropic, mobilizing a variety of signal transducers inside cells to produce a biological outcome. When the outcome in question is aldosterone production from the adrenal cortex, the main transducers activated specifically by the adrenocortical ATR to signal toward that cellular effect are the G protein alpha subunits and the β-arrestins (also known as Arrestin-2 and -3). The existence of various downstream pathways the ATR signal can travel down on has led to the ever-expanding filed of GPCR pharmacology termed "biased" signaling, which refers to a ligand preferentially activating one signaling pathway over others downstream of the same receptor in the same cell. However, "biased" signaling or "biased" agonism is therapeutically desirable only when the downstream pathways lead to different or opposite cellular outcomes, so the pathway promoting the beneficial effect can be selectively activated over the pathway that leads to detrimental consequences. In the case of the adrenal ATR, both G proteins and β-arrestins mediate signaling to the same end-result: aldosterone synthesis and secretion. Therefore, both pathways need to remain inactive in the adrenal cortex to fully suppress the production of aldosterone, which is one of the culprit hormones elevated in chronic heart failure, hypertension, and various other cardiovascular diseases. Variations in the effectiveness of the ATR antagonists, which constitute the angiotensin receptor blocker (ARB) class of drugs (also known as sartans), at the relative blockade of these two pathways downstream of the adrenal ATR opens the door to the flip term "biased" inverse agonism at the ATR. ARBs that are unbiased and equipotent inverse agonists for both G proteins and β-arrestins at this receptor, like candesartan and valsartan, are the most preferred agents with the best efficacy at reducing circulating aldosterone, thereby ameliorating heart failure. In the present review, the biased signaling of the adrenal ATR, particularly in relation to aldosterone production, is examined and the term "biased" inverse agonism at the ATR is introduced and explained, as a means of pharmacological categorization of the various agents within the ARB drug class.
血管紧张素II（AngII）通过两种不同的G蛋白偶联受体（GPCR）类型，即AT1R和AT2R，在体内发挥多种生理作用，并显著影响心血管稳态。虽然对AT2R的信号传导了解不多，但已知AT1R信号传导具有多效性，可动员细胞内的多种信号转导分子产生生物学结果。当所讨论的结果是肾上腺皮质产生醛固酮时，肾上腺皮质AT1R特异性激活以向该细胞效应发出信号的主要转导分子是G蛋白α亚基和β-抑制蛋白（也称为抑制蛋白-2和-3）。AT1R信号可以沿着多种下游途径传导，这导致了GPCR药理学中不断扩大的“偏向性”信号传导领域，该领域是指一种配体在同一细胞中优先激活同一受体下游的一条信号传导途径而不是其他途径。然而，只有当下游途径导致不同或相反的细胞结果时，“偏向性”信号传导或“偏向性”激动作用才在治疗上是可取的，这样促进有益作用的途径可以相对于导致有害后果的途径被选择性激活。就肾上腺AT1R而言，G蛋白和β-抑制蛋白都介导相同最终结果的信号传导：醛固酮的合成和分泌。因此，这两条途径在肾上腺皮质中都需要保持无活性，以完全抑制醛固酮的产生，醛固酮是慢性心力衰竭、高血压和各种其他心血管疾病中升高的罪魁祸首激素之一。构成血管紧张素受体阻滞剂（ARB）类药物（也称为沙坦类药物）的AT1R拮抗剂在肾上腺AT1R下游这两条途径的相对阻断效果上的差异，为AT1R上的相反术语“偏向性”反向激动作用打开了大门。在该受体上对G蛋白和β-抑制蛋白均为无偏向性且等效的反向激动剂的ARB，如坎地沙坦和缬沙坦，是在降低循环醛固酮从而改善心力衰竭方面疗效最佳的最优选药物。在本综述中，研究了肾上腺AT1R的偏向性信号传导，特别是与醛固酮产生相关的偏向性信号传导，并引入和解释了AT1R上的“偏向性”反向激动作用这一术语，作为ARB药物类别中各种药物的药理学分类方法。
