Regulatory role of some protein kinases in signal transduction pathways in heart health and disease

Q4 Medicine
M. Nusier, V. Elimban, Jaykishan Prasad, A. Shah, N. Dhalla
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引用次数: 1

Abstract

Various protein kinases including protein kinase A (PKA), Ca2+-calmodulin kinase (CaMK), phosphoinositide 3-kinase (PI3K), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK: ERK1/2, p38-MAPK and JNK) are integral part of different signal transduction pathways, which are known to regulate cardiac structure, function and metabolism. In addition, these signal transducing proteins are involved in the regulation of cation transport, cellular growth, gene expression, apoptosis and fibrosis by modifying the function of different target sites of subcellular organelles in the myocardium. However, the information regarding these signal transducing molecules is scattered and mechanisms of their involvement in diverse regulatory processes are poorly understood. While PKA, CaMK, PI3K and PKC are activated by different hormones and mechanical stimuli, MAPKs are activated by growth factors and some cellular stresses such as oxidative stress, inflammation and Ca2+-overload. Each type of these protein kinases is expressed in the form of two or more isozymes showing different biochemical characteristics and distinct biological functions. It has been demonstrated that all specific isoforms of these kinases produce both beneficial and detrimental effects on the heart, which are dependent upon the intensity and duration of stimulus for their activation. While PKA, PKC and CaMK are mainly involved in augmenting cardiac function as well as inducing cardiac hypertrophy and arrhythmias, PI3K is mainly involved in maintaining b-adrenoceptor function and inducing inflammation as well as arrhythmias. On the other hand, ERK1/2 mainly participate in the genesis of cardiac hypertrophy and cytoprotection whereas p38-MAPK and JNK are primarily involved in cardiac dysfunction, apoptosis and fibrosis. Since the activities of most protein kinases are increased under prolonged pathological conditions, a wide variety of their inhibitors have been shown to produce beneficial effects. However, extensive research needs to be carried out to understand the pathophysiology of different isoforms of each protein kinase as well as for the development of their isoform-specific inhibitors.
一些蛋白激酶在心脏健康和疾病信号转导通路中的调节作用
多种蛋白激酶包括蛋白激酶A (PKA)、Ca2+-钙调蛋白激酶(CaMK)、磷酸肌醇3-激酶(PI3K)、蛋白激酶C (PKC)和丝裂原活化蛋白激酶(MAPK: ERK1/2、p38-MAPK和JNK)是不同信号转导途径的组成部分,它们调节心脏的结构、功能和代谢。此外,这些信号转导蛋白通过改变心肌亚细胞细胞器不同靶点的功能,参与阳离子转运、细胞生长、基因表达、细胞凋亡和纤维化的调控。然而,关于这些信号转导分子的信息是分散的,它们参与各种调节过程的机制也知之甚少。PKA、CaMK、PI3K和PKC可被不同的激素和机械刺激激活,而MAPKs可被生长因子和一些细胞应激(如氧化应激、炎症和Ca2+超载)激活。每种类型的蛋白激酶都以两种或两种以上同工酶的形式表达,表现出不同的生化特性和不同的生物学功能。已经证明,这些激酶的所有特定亚型都对心脏产生有益和有害的影响,这取决于刺激它们激活的强度和持续时间。PKA、PKC和CaMK主要参与增强心功能,诱导心肌肥厚和心律失常,PI3K主要参与维持b-肾上腺素能受体功能,诱导炎症和心律失常。另一方面,ERK1/2主要参与心肌肥大和细胞保护的发生,而p38-MAPK和JNK主要参与心功能障碍、细胞凋亡和纤维化。由于大多数蛋白激酶的活性在长期的病理条件下增加,各种各样的它们的抑制剂已被证明能产生有益的效果。然而,需要进行广泛的研究来了解每种蛋白激酶的不同亚型的病理生理以及它们的亚型特异性抑制剂的开发。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
0.60
自引率
0.00%
发文量
13
审稿时长
4 weeks
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