β-arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes
β-arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes
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DOI：
10.1073/pnas.0607583103
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发表时间：
2006-10-31
影响因子：
11.1
通讯作者：
Lefkowitz, Robert J.
中科院分区：
文献类型：
--
作者：
Rajagopal, Keshava;Whalen, Erin J.;Lefkowitz, Robert J.
G蛋白偶联受体激酶（GRII（s）和β-抑制蛋白，通过七跨膜受体7 TMRS使G蛋白依赖性信号脱敏所必需的分子家族）最近已显示也抑制来自受体的G蛋白非依赖性信号。然而，这种G蛋白非依赖性、GRK/β-抑制蛋白依赖性信号传导的生理后果在很大程度上是未知的。在这里，我们建立了GRK/Parrestin介导的信号转导通过血管紧张素11（ANG）1A型受体（AT（1A）R）的结果，在分离的成年小鼠心肌细胞的正性肌力和lustropic效果。我们使用了“偏向性”AT（1A）R激动剂[Sar（1），IIe（4），Ile（8）]-血管紧张素II（SII），其不能刺激G（alpha）q介导的信号传导，但先前已显示其促进P-抑制蛋白与AT（1A）R的相互作用。来自WT而非AT（1A）R缺陷敲除（KO）小鼠的心肌细胞对ANG和Sill均表现出正性肌力和负性反应。WT心肌细胞对ANG的反应被蛋白激酶C（PKC）抑制显著降低，而对SII的反应不受影响。相比之下，来自β-arrestin 2 KO和GRK 6 KO小鼠的心肌细胞对SII没有反应，但对ANG显示出保留的反应。与ANG相比，GRK 2杂合敲除小鼠（GRK 2（+/-））的心肌细胞对SII的反应增强，而GRK 5 KO小鼠的心肌细胞与WT小鼠的心肌细胞无差异。这些发现表明存在独立的G α q/PKC和GRK 6/β-arrestin 2依赖性机制，通过该机制刺激AT（1A）R可以调节心肌细胞功能，并且可以通过选择性受体配体差异激活。这样的配体可能具有作为新型治疗剂的潜力。
The G protein-coupled receptor kinases (GRII(s) and beta-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/beta-arrestin-dependent signaling are largely unknown. Here, we establish that GRK/Parrestin-mediated signal transduction via the angiotensin 11 (ANG) type 1A receptor (AT(1A)R) results in positive inotropic and lusitropic effects in isolated adult mouse cardiomyocytes. We used the "biased" AT(1A)R agonist [Sar(1), IIe(4), Ile(8)]-angiotensin II (SII), which is unable to stimulate G(alpha)q-mediated signaling, but which has previously been shown to promote P-arrestin interaction with the AT(1A)R. Cardiomyocytes from WT, but not AT(1A)R-deficient knockout (KO) mice, exhibited positive inotropic and lusitropic responses to both ANG and Sill. Responses of WT cardiomyocytes to ANG were dramatically reduced by protein kinase C (PKC) inhibition, whereas those to SII were unaffected. In contrast, cardiomyocytes from beta-arrestin2 KO and GRK6 KO mice failed to respond to SII, but displayed preserved responses to ANG. Cardiomyocytes from GRK2 heterozygous knockout mice (GRK2(+/-)) exhibited augmented responses to SII in comparison to ANG, whereas those from GRK5 KO mice did not differ from those from WT mice. These findings indicate the existence of independent G alpha q/PKC- and GRK6/beta-arrestin2-dependent mechanisms by which stimulation of the AT(1A)R can modulate cardiomyocyte function, and which can be differentially activated by selective receptor ligands. Such ligands may have potential as a novel class of therapeutic agents.