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首页> 美国卫生研究院文献>American Journal of Physiology - Cell Physiology >Residues 248–252 and 300–304 of the cardiac Na+/Ca2+ exchanger are involved in its regulation by phospholemman
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Residues 248–252 and 300–304 of the cardiac Na+/Ca2+ exchanger are involved in its regulation by phospholemman

机译：心脏Na + / Ca2 +交换子的残基248-252和300-304参与了磷脂质调节

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摘要

Using split cardiac Na+/Ca2+ exchangers (NCX1), we previously demonstrated that phospholemman (PLM) regulates NCX1 by interacting with the proximal linker domain (residues 218–358) of the intracellular loop of NCX1. With the use of overlapping loop deletion mutants, interaction sites are localized to two regions spanning residues 238–270 and residues 300–328 of NCX1. In this study, we used alanine (Ala) linker scanning to pinpoint the residues in the proximal linker domain involved in regulation of NCX1 by PLM. Transfection of human embryonic kidney (HEK)293 cells with wild-type (WT) NCX1 or its Ala mutants but not empty vector resulted in NCX1 current (INaCa). Coexpression of PLM with WT NCX1 inhibited INaCa. Mutating residues 248–252 (PASKT) or 300–304 (QKHPD) in WT NCX1 to Ala resulted in loss of inhibition of INaCa by PLM. By contrast, inhibition of INaCa by PLM was preserved when residues 238–242, 243–247, 253–257, 258–262, 263–267, 305–309, 310–314, 315–319, 320–324, or 325–329 were mutated to Ala. While mutating residue 301 to alanine completely abolished PLM inhibition, mutation of any single residue 250–252, 300, or 302–304 resulted in partial reduction in inhibition. Mutating residues 248–252 to Ala resulted in significantly weaker association with PLM. The NCX1-G503P mutant that lacks Ca2+-dependent activation retained its sensitivity to PLM. We conclude that residues 248–252 and 300–304 in the proximal linker domain of NCX1 were involved in its inhibition by PLM.
机译：使用分裂的心脏Na + / Ca 2 + 交换子（NCX1），我们先前证明了磷脂质（PLM）通过与近端接头结构域相互作用来调节NCX1（残基218-358） ）的NCX1细胞内环。通过使用重叠的环缺失突变体，相互作用位点位于NCX1的残基238-270和残基300-328的两个区域。在这项研究中，我们使用丙氨酸（Ala）接头扫描来查明参与PLM调控NCX1的近端接头结构域中的残基。用野生型（WT）NCX1或其Ala突变体而非空载体转染人胚肾（HEK）293细胞导致NCX1电流（INaCa）。 PLM与WT NCX1共表达可抑制INaCa。将WT NCX1中的248-252（PASKT）或300-304（QKHPD）残基突变为Ala会导致PLM对INaCa的抑制作用丧失。相反，当残基238-242、243-247、253-257、258-262、263-267、305-309、310-314、315-319、320-324或325时，保留了PLM对INaCa的抑制作用。 –329突变为Ala，虽然将残基301突变为丙氨酸完全消除了PLM抑制作用，但任何单个残基250-252、300或302-304的突变都会导致抑制作用部分降低。将248-252位残基突变为Ala导致与PLM的关联显着减弱。缺少Ca 2 + 依赖性激活的NCX1-G503P突变体保留了其对PLM的敏感性。我们得出的结论是，NCX1的近端接头域中的残基248–252和300–304与PLM的抑制有关。

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