Regulation by phosphodiesterase isoforms of protein kinase A-mediated attenuation of myocardial protein kinase D activation.
Regulation by phosphodiesterase isoforms of protein kinase A-mediated attenuation of myocardial protein kinase D activation.
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DOI：
10.1007/s00395-010-0116-1
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发表时间：
2011-01
影响因子：
9.5
通讯作者：
Avkiran M
中科院分区：
文献类型：
--
作者：
Haworth RS;Cuello F;Avkiran M
蛋白激酶D(PKD)针对心脏中的几种蛋白质，包括心肌肌钙蛋白I(CTnI)和II类组蛋白去乙酰基酶，调节心肌收缩和肥厚。在成年大鼠的心室肌细胞中，内皮素-1通过蛋白激酶Cε激活蛋白激酶D，并被cAMP依赖的蛋白激酶减弱。由于不同的环核苷酸磷酸二酯酶(PDE)亚型的局部活性，cAMP在细胞内的区域化可能导致对PKA活性的空间受限调节，从而抑制PKD的激活。我们研究了主要的心脏PDE亚型，PDE2，PDE3和PDE4，在PKA介导的抑制PKD激活中的作用。用非选择性PDE抑制剂异丁基甲基黄嘌呤(IBMX)预处理ARVM可减弱ET1对随后的PKD的激活。但选择性抑制PDE2、PDE3(西洛胺)或PDE4(罗利普兰)对ET1诱导的PKD激活无影响。选择性抑制单个PDE亚型也不影响已建立的心肌PKA底物磷脂蛋白(PLB；在Ser16)和cTnI(在Ser22/23)的磷酸化状态，这两种蛋白的磷酸化状态随着IBMX的增加而显著增加。西洛胺和罗利普兰联合应用，如单用IBMX，可减弱ET1诱导的PKD激活，增加pLB和cTnI的磷酸化，而eHNA和西洛司胺或eHNA和罗利普兰联合应用则无效。因此，由PDE3和PDE4控制的cAMP池而不是由PDE2控制的cAMP池调节PKA活性，从而抑制ET1诱导的PKD激活。此外，PDE3和PDE4在这一过程中扮演着多余的角色，因此需要抑制这两种异构体才能实现PKA介导的PKD激活的减弱。
Protein kinase D (PKD) targets several proteins in the heart, including cardiac troponin I (cTnI) and class II histone deacetylases, and regulates cardiac contraction and hypertrophy. In adult rat ventricular myocytes (ARVM), PKD activation by endothelin-1 (ET1) occurs via protein kinase Cε and is attenuated by cAMP-dependent protein kinase (PKA). Intracellular compartmentalisation of cAMP, arising from localised activity of distinct cyclic nucleotide phosphodiesterase (PDE) isoforms, may result in spatially constrained regulation of the PKA activity that inhibits PKD activation. We have investigated the roles of the predominant cardiac PDE isoforms, PDE2, PDE3 and PDE4, in PKA-mediated inhibition of PKD activation. Pretreatment of ARVM with the non-selective PDE inhibitor isobutylmethylxanthine (IBMX) attenuated subsequent PKD activation by ET1. However, selective inhibition of PDE2 [by erythro-9-(2-hydroxy-3-nonyl) adenine, EHNA], PDE3 (by cilostamide) or PDE4 (by rolipram) individually had no effect on ET1-induced PKD activation. Selective inhibition of individual PDE isoforms also had no effect on the phosphorylation status of the established cardiac PKA substrates phospholamban (PLB; at Ser16) and cTnI (at Ser22/23), which increased markedly with IBMX. Combined administration of cilostamide and rolipram, like IBMX alone, attenuated ET1-induced PKD activation and increased PLB and cTnI phosphorylation, while combined administration of EHNA and cilostamide or EHNA and rolipram was ineffective. Thus, cAMP pools controlled by PDE3 and PDE4, but not PDE2, regulate the PKA activity that inhibits ET1-induced PKD activation. Furthermore, PDE3 and PDE4 play redundant roles in this process, such that inhibition of both isoforms is required to achieve PKA-mediated attenuation of PKD activation.
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影响因子：
20.1
作者：
Nikolaev, Viacheslav O.;Buenemann, Moritz;Engelhardt, Stefan
通讯作者：
Engelhardt, Stefan
影响因子：
5
作者：
Haworth, RS;Goss, MW;Avkiran, M
通讯作者：
Avkiran, M
磷酸二酯酶4和磷酸酶2a差异调节CAMP/蛋白激酶A信号在刺激β1肾上腺素能受体下进行心肌细胞收缩。
影响因子：
3.6
作者：
De Arcangelis V;Soto D;Xiang Y
通讯作者：
Xiang Y
影响因子：
5.3
作者：
Harrison, Brooke C.;Kim, Mi-Sung;McKinsey, Timothy A.
通讯作者：
McKinsey, Timothy A.
影响因子：
20.1
作者：
Leroy, Jerome;Abi-Gerges, Aniella;Vandecasteele, Gregoire
通讯作者：
Vandecasteele, Gregoire