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首页> 外文会议>Sodium-Calcium Exchange and the Plasma Membrane Ca~(2+)- ATPase in Cell Function; Annals of the New York Academy of Sciences; vol.1099 >Regulation of Cardiac Na~+/Ca~(2+) Exchanger by Phospholemman
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Regulation of Cardiac Na~+/Ca~(2+) Exchanger by Phospholemman

机译：磷脂分子对心脏Na〜+ / Ca〜（2+）交换子的调节

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摘要

Phospholemman (PLM) is the first sequenced member of the FXYD family of regulators of ion transport. The mature protein has 72 amino acids and consists of an extracellular N terminus containing the signature FXYD motif, a single transmembrane (TM) domain, and a cytoplasmic C-terminal domain containing four potential sites for phosphorylation. PLM and other members of the FXYD family are known to regulate Na~+-K~+-ATPase. Using adenovirus-mediated gene transfer into adult rat cardiac myocytes, we showed that changes in contractility and intracellular Ca~(2+) homeostasis associated with PLM overexpression or downregulation are not consistent with the effects expected from inhibition of Na~+-K~+-ATPase by PLM. Additional studies with heterologous expression of PLM and cardiac Na~+/Ca~(2+) exchanger 1 (NCX1) in HEK293 cells and cardiac myocytes isolated from PLM-deficient mice demonstrated by co-localization, co-immunoprecipitation, and electrophysiological and radioactive tracer uptake techniques that PLM associates with NCX1 in the sarcolemma and transverse tubules and that PLM inhibits NCX1, independent of its effects on Na~+-K~+-ATPase. Mutational analysis indicates that the cytoplasmic domain of PLM is required for its regulation of NCX1. In addition, experiments using phosphomimetic and phospho-deficient PLM mutants, as well as activators of protein kinases A and C, indicate that PLM phosphory-lated at serine68 is the active form that inhibits NCX1. This is in sharp contrast to the finding that the unphosphorylated PLM form inhibits Na~+-K~+-ATPase. We conclude that PLM regulates cardiac contractility by modulating the activities of NCX and Na~+-K~+-ATPase.
机译：Phlempholemman（PLM）是FXYD离子迁移调节剂家族的第一个序列成员。成熟的蛋白质有72个氨基酸，由含有标志性FXYD基序的细胞外N端，单个跨膜（TM）域和包含四个潜在磷酸化位点的胞质C末端域组成。已知PLM和FXYD家族的其他成员调节Na〜+ -K〜+ -ATPase。使用腺病毒介导的基因转移到成年大鼠心肌细胞中，我们发现与PLM过表达或下调相关的收缩力和细胞内Ca〜（2+）动态平衡的变化与Na〜+ -K〜+的抑制作用预期的不一致-ATPase by PLM。通过共定位，共免疫沉淀，电生理和放射性证明了从PLM缺陷小鼠分离的HEK293细胞和心肌细胞中PLM和心脏Na〜+ / Ca〜（2+）交换子1（NCX1）异源表达的其他研究示踪剂摄取技术，PLM与肌膜和横管中的NCX1相关联，并且PLM抑制NCX1，而不受其对Na〜+ -K〜+ -ATPase的影响。突变分析表明，PLM的胞质结构域是调控NCX1所必需的。此外，使用模拟磷酸和磷酸缺失的PLM突变体以及蛋白激酶A和C的激活剂进行的实验表明，丝氨酸68磷酸化的PLM是抑制NCX1的活性形式。这与未磷酸化的PLM形式抑制Na〜+ -K〜+ -ATPase的发现形成鲜明对比。我们得出结论，PLM通过调节NCX和Na〜+ -K〜+ -ATPase的活性来调节心脏收缩力。

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