As the largest membrane protein family encoded by human genome, G protein-coupled receptors (GPCRs) regulate almost all known physiological processes and are considered the most important drug target. Angiotensin II receptor type 1 (AT1R), a key component of the renin-angiotensin system, plays a critical regulatory role in various physiological processes such as vasoconstriction and aldosterone secretion. The AT1R was known to sense the octapeptide angiotensin II (AngII), which is converted from angiotensin I by angiotensin-converting enzyme (ACE), to initiate Gq, Gi and arrestin signaling to regulate vascular resistance, cardiac output, inflammatory response and gastrointestinal functions. However, whether AT1R could sense other endogenous ligands and how specific downstream signaling of AT1R are organized to precisely regulate different physiological functions required further delineation.
Recently, we have identified homocysteine (hcy) and cartilage oligomeric matrix protein (COMP) as endogenous ligands of AT1R1,2. Whereas the hcy partially activates AT1R and synergistically increases AngII-induced vascular injury, the COMP acts as an endogenous allosteric biased modulator and counteracts the vascular injury by selectively blocking β-arrestin-2 pathway. We also found that β-arrestin-1 biased ligand stimulation promotes the direct coupling of AT1R to ion channel TRPC3 and regulates acute catecholamine secretion from chromaffin cells, which might be linked to higher risk of hypertension3. Moreover, by a combined computational and experimental framework, we unprecedently identified a cryptic allosteric site in AT1R, which might be targeted to develop allosteric modulators4.
Collectively, our results identified novel endogenous ligands of AT1R, delineated the molecular mechanism underlying AT1R biased signaling, and shed light on the development of selective modulators. These findings provide a deeper understanding of AT1R activation and might reveal novel therapeutic strategies for cardiovascular diseases.
 

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