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The G protein-coupled receptor kinases (GRKs) and β-arrestins, families of molecules essential to the desensitization of G protein-dependent signaling via seven-transmembrane receptors (7TMRs), have been recently shown to also transduce G protein-independent signals from receptors. However, the physiologic consequences of this G protein-independent, GRK/β-arrestin-dependent signaling are largely unknown. Here, we establish that GRK/β-arrestin-mediated signal transduction via the angiotensin II (ANG) type 1A receptor (AT_1AR) results in positive inotropic and lusitropic effects in isolated adult mouse cardiomyocytes. We used the “biased” AT_1AR agonist [Sar¹, Ile⁴, Ile⁸]-angiotensin II (SII), which is unable to stimulate G_αq-mediated signaling, but which has previously been shown to promote β-arrestin interaction with the AT_1AR. Cardiomyocytes from WT, but not AT_1AR-deficient knockout (KO) mice …