Protein kinase D (PKD) consists of a family of three structurally related enzymes that play key roles in a wide range of biological functions that contribute to the evolution of cardiac hypertrophy and heart failure. PKD1 (the founding member of this enzyme family) has been implicated in the phosphorylation of substrates that regulate cardiac hypertrophy, contraction, and susceptibility to ischemia/reperfusion injury, and de novo PRKD1 (protein kinase D1 gene) mutations have been identified in patients with syndromic congenital heart disease. However, cardiomyocytes coexpress all three PKDs. Although stimulus-specific activation patterns for PKD1, PKD2, and PKD3 have been identified in cardiomyocytes, progress toward identifying PKD isoform-specific functions in the heart have been hampered by significant gaps in our understanding of the molecular mechanisms that regulate PKD activity. This review incorporates recent conceptual breakthroughs in our understanding of various alternative mechanisms for PKD activation, with an emphasis on recent evidence that PKDs activate certain effector responses as dimers, to consider the role of PKD isoforms in signaling pathways that drive cardiac hypertrophy and ischemia/reperfusion injury. The focus is on whether the recently identified activation mechanisms that enhance the signaling repertoire of PKD family enzymes provide novel therapeutic strategies to target PKD enzymes and prevent or slow the evolution of cardiac injury and pathological cardiac remodeling.

中文翻译：

---

解码蛋白激酶 D 亚型的心脏作用

蛋白激酶 D (PKD) 由三种结构相关的酶组成，这些酶在广泛的生物学功能中发挥关键作用，这些生物学功能有助于心脏肥大和心力衰竭的演变。PKD1（该酶家族的创始成员）与调节心脏肥大、收缩和对缺血/再灌注损伤的易感性的底物磷酸化有关，以及从头开始 PRKD1（蛋白激酶 D1 基因）突变已在先天性心脏病患者中发现。然而，心肌细胞共表达所有三种 PKD。尽管已在心肌细胞中鉴定出 PKD1、PKD2 和 PKD3 的刺激特异性激活模式，但我们对调节 PKD 活性的分子机制的理解存在重大差距，阻碍了鉴定心脏中 PKD 亚型特异性功能的进展。这篇综述结合了我们对 PKD 激活的各种替代机制的理解的最新概念突破，重点是最近的证据表明 PKD 将某些效应反应激活为二聚体，以考虑 PKD 亚型在驱动心脏肥大和缺血/再灌注的信号通路中的作用受伤。