Golgi localized β1-adrenergic receptors stimulate Golgi PI4P hydrolysis by PLCε to regulate cardiac hypertrophy
Golgi localized β1-adrenergic receptors stimulate Golgi PI4P hydrolysis by PLCε to regulate cardiac hypertrophy
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DOI：
10.7554/elife.48167
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发表时间：
2019-08-21
期刊：
影响因子：
7.7
通讯作者：
Smrcka, Alan V.
中科院分区：
文献类型：
--
作者：
Nash, Craig A.;Wei, Wenhui;Smrcka, Alan V.
心血管应激导致的肾上腺素能紧张度增加导致心力衰竭的发展，部分原因是通过慢性刺激心肌细胞上的β 1肾上腺素能受体（β AR）。阻断这些受体是β受体阻滞剂治疗心力衰竭的基础之一。最近的数据表明，G蛋白偶联受体（GPCR），包括β AR，在细胞内被激活，尽管生物学意义尚不清楚。在这里，我们研究了高尔基体β AR在大鼠心肌细胞中的功能作用，发现它们激活高尔基体局部的、促肥大的磷酸肌醇水解，这是细胞表面β AR刺激所不能达到的。该途径由生理神经递质去甲肾上腺素（NE）通过Oct3有机阳离子转运蛋白进入。阻断Oct3或特异性阻断高尔基体驻留β 1 AR可预防NE依赖性心肌细胞肥大。这清楚地定义了生物学相关细胞类型中由内部GPCR激活的途径，并对开发更有效的β受体阻滞剂疗法具有意义。
Increased adrenergic tone resulting from cardiovascular stress leads to development of heart failure, in part, through chronic stimulation of beta 1 adrenergic receptors (beta ARs) on cardiac myocytes. Blocking these receptors is part of the basis for beta-blocker therapy for heart failure. Recent data demonstrate that G protein-coupled receptors (GPCRs), including beta ARs, are activated intracellularly, although the biological significance is unclear. Here we investigated the functional role of Golgi beta ARs in rat cardiac myocytes and found they activate Golgi localized, prohypertrophic, phosphoinositide hydrolysis, that is not accessed by cell surface beta AR stimulation. This pathway is accessed by the physiological neurotransmitter norepinephrine (NE) via an Oct3 organic cation transporter. Blockade of Oct3 or specific blockade of Golgi resident beta 1ARs prevents NE dependent cardiac myocyte hypertrophy. This clearly defines a pathway activated by internal GPCRs in a biologically relevant cell type and has implications for development of more efficacious beta-blocker therapies.