<p class="first" id="P1">Although the octapeptide hormone angiotensin II (Ang II)
regulates cardiovascular
and renal homeostasis through the Ang II type 1 receptor (AT1R), overstimulation of
AT1R causes various human diseases, such as hypertension and cardiac hypertrophy.
Therefore, AT1R blockers (ARBs) have been widely used as therapeutic drugs for these
diseases. Recent basic research and clinical studies have resulted in the discovery
of interesting phenomena associated with AT1R function. For example, ligand-independent
activation of AT1R by mechanical stress and agonistic autoantibodies, as well as via
receptor mutations, has been shown to decrease the inverse agonistic efficacy of ARBs,
though the molecular mechanisms of such phenomena had remained elusive until recently.
Furthermore, although AT1R is believed to exist as a monomer, recent studies have
demonstrated that AT1R can homodimerize and heterodimerize with other G-protein coupled
receptors (GPCR), altering the receptor signaling properties. Therefore, formation
of both AT1R homodimers and AT1R-GPCR heterodimers may be involved in the pathogenesis
of human disease states, such as atherosclerosis and preeclampsia. Finally, biased
AT1R ligands that can preferentially activate the β-arrestin-mediated signaling pathway
have been discovered. Such β-arrestin-biased AT1R ligands may be better therapeutic
drugs for cardiovascular diseases. New findings on AT1R described herein could provide
a conceptual framework for application of ARBs in the treatment of diseases, as well
as for novel drug development. Since AT1R is an extensively studied member of the
GPCR superfamily encoded in the human genome, this review is relevant for understanding
the functions of other members of this superfamily.
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