Alican Güran , Yanlong Ji , Pan Fang , Kuan-Ting Pan , Henning Urlaub , Metin Avkiran , Christof Lenz , Kate L. Weeks
{"title":"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","authors":"Alican Güran , Yanlong Ji , Pan Fang , Kuan-Ting Pan , Henning Urlaub , Metin Avkiran , Christof Lenz , Kate L. Weeks","doi":"10.1016/j.jmccpl.2025.100301","DOIUrl":null,"url":null,"abstract":"<div><div>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 <em>in vivo</em>, 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 Ca<sup>2+</sup> 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.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"12 ","pages":"Article 100301"},"PeriodicalIF":0.0000,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"PP2A-B56α is a key determinant of cardiac protein phosphorylation and functional responses to β-adrenergic signalling\",\"authors\":\"Alican Güran , Yanlong Ji , Pan Fang , Kuan-Ting Pan , Henning Urlaub , Metin Avkiran , Christof Lenz , Kate L. Weeks\",\"doi\":\"10.1016/j.jmccpl.2025.100301\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>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 <em>in vivo</em>, 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 Ca<sup>2+</sup> 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.</div></div>\",\"PeriodicalId\":73835,\"journal\":{\"name\":\"Journal of molecular and cellular cardiology plus\",\"volume\":\"12 \",\"pages\":\"Article 100301\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2025-05-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of molecular and cellular cardiology plus\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2772976125000200\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of molecular and cellular cardiology plus","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2772976125000200","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
PP2A-B56α is a key determinant of cardiac protein phosphorylation and functional responses to β-adrenergic signalling
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.