a Institute of Cardiovascular and Medical Sciences , University of Glasgow , Glasgow , UK.
b Molecular and Clinical Medicine , University of Dundee , Dundee , UK.
Crit Rev Biochem Mol Biol. 2018 Apr;53(2):175-191. doi: 10.1080/10409238.2018.1432560. Epub 2018 Feb 9.
The ubiquitous sodium/potassium ATPase (Na pump) is the most abundant primary active transporter at the cell surface of multiple cell types, including ventricular myocytes in the heart. The activity of the Na pump establishes transmembrane ion gradients that control numerous events at the cell surface, positioning it as a key regulator of the contractile and metabolic state of the myocardium. Defects in Na pump activity and regulation elevate intracellular Na in cardiac muscle, playing a causal role in the development of cardiac hypertrophy, diastolic dysfunction, arrhythmias and heart failure. Palmitoylation is the reversible conjugation of the fatty acid palmitate to specific protein cysteine residues; all subunits of the cardiac Na pump are palmitoylated. Palmitoylation of the pump's accessory subunit phospholemman (PLM) by the cell surface palmitoyl acyl transferase DHHC5 leads to pump inhibition, possibly by altering the relationship between the pump catalytic α subunit and specifically bound membrane lipids. In this review, we discuss the functional impact of PLM palmitoylation on the cardiac Na pump and the molecular basis of recognition of PLM by its palmitoylating enzyme DHHC5, as well as effects of palmitoylation on Na pump cell surface abundance in the cardiac muscle. We also highlight the numerous unanswered questions regarding the cellular control of this fundamentally important regulatory process.
无处不在的钠/钾 ATP 酶（Na 泵）是多种细胞类型表面最丰富的原发性主动转运体，包括心脏中的心室肌细胞。Na 泵的活性建立了跨膜离子梯度，控制着细胞表面的许多事件，使其成为心肌收缩和代谢状态的关键调节剂。Na 泵活性和调节的缺陷会导致心肌细胞内 Na 升高，在心肌肥厚、舒张功能障碍、心律失常和心力衰竭的发展中起因果作用。棕榈酰化是脂肪酸棕榈酸可逆地与特定蛋白半胱氨酸残基结合的过程；心脏 Na 泵的所有亚基都被棕榈酰化。细胞质面棕榈酰转移酶 DHHC5 对泵的辅助亚基磷酯酶 M（PLM）的棕榈酰化导致泵抑制，可能是通过改变泵催化α亚基与特定结合膜脂质之间的关系。在这篇综述中，我们讨论了 PLM 棕榈酰化对心脏 Na 泵的功能影响，以及其棕榈酰化酶 DHHC5 识别 PLM 的分子基础，以及棕榈酰化对心肌中 Na 泵细胞表面丰度的影响。我们还强调了关于这个基本重要调节过程的细胞控制的许多未解决的问题。
