Adrenal angiotensin II type 1 receptor biased signaling: The case for "biased" inverse agonism for effective aldosterone suppression.

Angiotensin II (AngII) uses two distinct G protein-coupled receptor (GPCR) types, AT1R and AT2R, 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 AT2R, AT1R 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 AT1R to signal toward that cellular effect are the Gq/11 protein alpha subunits and the β-arrestins (also known as Arrestin-2 and -3). The existence of various downstream pathways the AT1R 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 AT1R, both Gq/11 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 AT1R 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 AT1R opens the door to the flip term "biased" inverse agonism at the AT1R. 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 AT1R, particularly in relation to aldosterone production, is examined and the term "biased" inverse agonism at the AT1R is introduced and explained, as a means of pharmacological categorization of the various agents within the ARB drug class.