Essandoh Kobina, Philippe Julie M, Jenkins Paul M, Brody Matthew J
Department of Pharmacology, University of Michigan, Ann Arbor, MI, United States.
Department of Psychiatry, University of Michigan, Ann Arbor, MI, United States.
Front Physiol. 2020 Feb 19;11:108. doi: 10.3389/fphys.2020.00108. eCollection 2020.
Regulation of cardiac physiology is well known to occur through the action of kinases that reversibly phosphorylate ion channels, calcium handling machinery, and signaling effectors. However, it is becoming increasingly apparent that palmitoylation or S-acylation, the post-translational modification of cysteines with saturated fatty acids, plays instrumental roles in regulating the localization, activity, stability, sorting, and function of numerous proteins, including proteins known to have essential functions in cardiomyocytes. However, the impact of this modification on cardiac physiology requires further investigation. S-acylation is catalyzed by the zDHHC family of S-acyl transferases that localize to intracellular organelle membranes or the sarcolemma. Recent work has begun to uncover functions of S-acylation in the heart, particularly in the regulation of cardiac electrophysiology, including modification of the sodium-calcium exchanger, phospholemman and the cardiac sodium pump, as well as the voltage-gated sodium channel. Elucidating the regulatory functions of zDHHC enzymes in cardiomyocytes and determination of how S-acylation is altered in the diseased heart will shed light on how these modifications participate in cardiac pathogenesis and potentially identify novel targets for the treatment of cardiovascular disease. Indeed, proteins with critical signaling roles in the heart are also S-acylated, including receptors and G-proteins, yet the dynamics and functions of these modifications in myocardial physiology have not been interrogated. Here, we will review what is known about zDHHC enzymes and substrate S-acylation in myocardial physiology and highlight future areas of investigation that will uncover novel functions of S-acylation in cardiac homeostasis and pathophysiology.
心脏生理学的调节是通过激酶的作用实现的，这些激酶可使离子通道、钙处理机制和信号效应器发生可逆的磷酸化。然而，越来越明显的是，棕榈酰化或S-酰化（即半胱氨酸与饱和脂肪酸的翻译后修饰）在调节众多蛋白质的定位、活性、稳定性、分选和功能方面发挥着重要作用，这些蛋白质包括已知在心肌细胞中具有重要功能的蛋白质。然而，这种修饰对心脏生理学的影响还需要进一步研究。S-酰化由定位于细胞内细胞器膜或肌膜的zDHHC家族S-酰基转移酶催化。最近的研究开始揭示S-酰化在心脏中的功能，特别是在心脏电生理调节方面，包括对钠钙交换体、磷膜蛋白和心脏钠泵以及电压门控钠通道的修饰。阐明zDHHC酶在心肌细胞中的调节功能以及确定患病心脏中S-酰化如何改变，将有助于了解这些修饰如何参与心脏发病机制，并有可能确定心血管疾病治疗的新靶点。事实上，在心脏中具有关键信号作用的蛋白质也会发生S-酰化，包括受体和G蛋白，但这些修饰在心肌生理学中的动态变化和功能尚未得到研究。在这里，我们将综述关于zDHHC酶和心肌生理学中底物S-酰化的已知信息，并强调未来的研究领域，这些领域将揭示S-酰化在心脏稳态和病理生理学中的新功能。
