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首页> 美国卫生研究院文献>other >Palmitoylation Regulates Intracellular Trafficking of β2 Adrenergic Receptor/Arrestin/Phosphodiesterase 4D Complexes in Cardiomyocytes
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Palmitoylation Regulates Intracellular Trafficking of β2 Adrenergic Receptor/Arrestin/Phosphodiesterase 4D Complexes in Cardiomyocytes

机译：棕榈调控对细胞内运输β2肾上腺素受体/休止/磷酸二酯酶4D场馆在心肌细胞

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摘要

β2 adrenergic receptor (β2AR) is a prototypical G-protein coupled receptor that stimulates the classic cAMP-protein kinase A (PKA) signaling pathway. Recent studies indicate that the cAMP-PKA activities are spatiotemporally regulated in part due to dynamic association of β2AR with phosphodiesterase 4D (PDE4D), a group of cAMP degradation enzymes. Here, we demonstrate that in cardiomyocytes, palmitoylation of β2AR, the covalent acylation of cysteine residue 341, plays a critical role in shaping subcellular cAMP-PKA activities in cardiomyocytes via regulating β2AR association with arrestin/PDE4D. Replacing cysteine 341 on β2AR with alanine (C341A) leads to an impaired binding to β arrestin 2. Surprisingly, the C341A mutant is able to internalize via an arrestin-independent pathway at saturated concentration of agonist stimulation; the internalization becomes caveolae-dependent and requires dynamin GTPase. However, the impaired binding to β arrestin 2 also leads to an impaired recruitment of PDE4D to the C341A mutant. Thus, the mutant C341A β2AR is transported alone from the plasma membrane to the endosome without recruiting PDE4D. This alteration leads to an enhanced cytoplasmic cAMP signal for PKA activation under β2AR stimulation. Functionally, Mutation of the C341 residue or inhibition of palmitoylation modification of β2AR enhances the receptor-induced PKA activities in the cytoplasm and increases in myocyte contraction rate. Our data reveal a novel function of palmitoylation in shaping subcellular cAMP-PKA signaling in cardiomyocytes via modulating the recruitment of β arrestin 2-PDE4D complexes to the agonist-stimulated β2AR.
机译：β2肾上腺素能受体（β2AR）是典型的G蛋白偶联受体，可刺激经典的cAMP蛋白激酶A（PKA）信号传导途径。最近的研究表明，cAMP-PKA活性受到时空调节，部分原因是β2AR与一组磷酸二酯酶4D（PDE4D）（一组cAMP降解酶）动态相关。在这里，我们证明了在心肌细胞中，β2AR的棕榈酰化，半胱氨酸残基341的共价酰化，通过调节β2AR与抑制蛋白/ PDE4D的结合，在塑造心肌细胞亚细胞cAMP-PKA活性中起着关键作用。用丙氨酸（C341A）替代β2AR上的半胱氨酸341会导致与β抑制蛋白2的结合受损。内部化成为小窝依赖的，并需要动力蛋白GTPase。但是，与β抑制蛋白2的结合受损也会导致PDE4D向C341A突变体募集受损。因此，突变体C341Aβ2AR单独从质膜转运至内体而不募集PDE4D。这种改变导致β2AR刺激下用于PKA活化的细胞质cAMP信号增强。在功能上，C341残基的突变或β2AR的棕榈酰化修饰的抑制增强了细胞质中受体诱导的PKA活性，并增加了心肌细胞的收缩率。我们的数据揭示了通过调节β抑制蛋白2-PDE4D复合物向激动剂刺激的β2AR的募集，棕榈酰化在塑造心肌细胞亚细胞cAMP-PKA信号中的新功能。

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