PP2A-B56α is a key determinant of cardiac protein phosphorylation and functional responses to β-adrenergic signalling

Alican Güran , Yanlong Ji , Pan Fang , Kuan-Ting Pan , Henning Urlaub , Metin Avkiran , Christof Lenz , Kate L. Weeks
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Abstract

B56α is a protein phosphatase 2 A (PP2A) regulatory subunit which modulates the heart's inotropic response to acute β-adrenergic receptor (β-AR) stimulation, although knowledge of the underlying molecular mechanisms is limited. In this study, mice deficient for B56α and wildtype controls received an intraperitoneal injection of isoproterenol (0.1 mg/kg) to activate β-AR signalling in vivo, and their hearts examined two minutes post-injection by quantitative phosphoproteomics to identify mechanisms of acute β-adrenergic signalling. We identified site- and genotype-specific phosphorylation changes on >200 proteins, including 25 hyperphosphorylated proteins harbouring a B56 binding motif as putative substrates. Functional enrichment analysis pointed to cardiac Ca2+ release and contractility as key processes impacted by B56α deficiency, as well as cardiac muscle hypertrophy as a potential disease mechanism. In vitro, loss of B56α in cardiomyocytes blunted acute isoproterenol-induced increases in intracellular calcium transient amplitude, confirming that B56α plays a key role in calcium handling. In vivo, loss of B56α protected mice from developing systolic dysfunction in response to sustained isoproterenol infusion (60 mg/kg/day for 14 days), despite comparable increases in heart mass. These findings reaffirm a key role for B56α as a mediator of physiologically important cardiac responses to β-AR stimulation and reveal potential new molecular mechanisms for this regulatory function, including putative cardiac B56α substrates.
PP2A-B56α是心脏蛋白磷酸化和β-肾上腺素能信号功能反应的关键决定因素
B56α是一种蛋白磷酸酶2a (PP2A)调节亚基,可调节心脏对急性β-肾上腺素能受体(β-AR)刺激的肌力反应,尽管对其潜在的分子机制了解有限。在这项研究中,B56α缺乏的小鼠和野生型对照组在体内腹腔注射异丙肾上腺素(0.1 mg/kg)来激活β-AR信号,注射后两分钟,通过定量磷蛋白质组学检查它们的心脏,以确定急性β-肾上腺素能信号传导的机制。我们在200个蛋白上发现了位点和基因型特异性磷酸化变化,包括25个含有B56结合基序的过度磷酸化蛋白作为推定底物。功能富集分析指出,心肌Ca2+释放和收缩力是受B56α缺乏影响的关键过程,心肌肥大是潜在的疾病机制。在体外,心肌细胞中B56α的缺失减弱了异丙肾上腺素诱导的急性细胞内钙瞬态振幅的增加,证实了B56α在钙处理中起关键作用。在体内,尽管心脏质量增加,但在持续输注异丙肾上腺素(60 mg/kg/天,持续14天)的小鼠中,B56α的缺失保护小鼠不发生收缩功能障碍。这些发现重申了B56α作为心脏对β-AR刺激的重要生理反应的介质的关键作用,并揭示了这种调节功能的潜在新分子机制,包括假定的心脏B56α底物。
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来源期刊
Journal of molecular and cellular cardiology plus
Journal of molecular and cellular cardiology plus Cardiology and Cardiovascular Medicine
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