Laudette Marion, Formoso Karina, Lezoualc'h Frank
INSERM UMR-1048, Institute of Metabolic and Cardiovascular Diseases, Université de Toulouse III-Paul Sabatier, 31432 Toulouse, France.
Cells. 2021 Jan 14;10(1):154. doi: 10.3390/cells10010154.
β-adrenergic receptors (β-ARs) play a major role in the physiological regulation of cardiac function through signaling routes tightly controlled by G protein-coupled receptor kinases (GRKs). Although the acute stimulation of β-ARs and the subsequent production of cyclic AMP (cAMP) have beneficial effects on cardiac function, chronic stimulation of β-ARs as observed under sympathetic overdrive promotes the development of pathological cardiac remodeling and heart failure (HF), a leading cause of mortality worldwide. This is accompanied by an alteration in cAMP compartmentalization and the activation of the exchange protein directly activated by cAMP 1 (Epac1) signaling. Among downstream signals of β-ARs, compelling evidence indicates that GRK2, GRK5, and Epac1 represent attractive therapeutic targets for cardiac disease. Here, we summarize the pathophysiological roles of GRK2, GRK5, and Epac1 in the heart. We focus on their signalosome and describe how under pathological settings, these proteins can cross-talk and are part of scaffolded nodal signaling systems that contribute to a decreased cardiac function and HF development.
β-肾上腺素能受体（β-ARs）通过由G蛋白偶联受体激酶（GRKs）严格控制的信号通路，在心脏功能的生理调节中发挥主要作用。虽然β-ARs的急性刺激以及随后环磷酸腺苷（cAMP）的产生对心脏功能有有益影响，但在交感神经过度兴奋情况下观察到的β-ARs慢性刺激会促进病理性心脏重塑和心力衰竭（HF）的发展，心力衰竭是全球主要的死亡原因。这伴随着cAMP区室化的改变以及由cAMP直接激活的交换蛋白1（Epac1）信号的激活。在β-ARs的下游信号中，有力证据表明GRK2、GRK5和Epac1是心脏病有吸引力的治疗靶点。在此，我们总结GRK2、GRK5和Epac1在心脏中的病理生理作用。我们关注它们的信号体，并描述在病理情况下，这些蛋白如何相互作用，以及它们是如何成为有助于心脏功能下降和心力衰竭发展的支架节点信号系统的一部分。
