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FKBP12.6 and cADPR regulation of Ca~(2+)release in smooth muscle cells

机译:FKBP12.6和cADPR调节平滑肌细胞中Ca〜(2+)的释放

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Intracellular Ca~(2+) release through ryanodine receptors (RyRs) plays important roles in smooth muscle excitation-contraction coupling, but the underlying regulatory mechanisms are poorly understood. Here we show that FK506 binding protein of 12.6 kDa (FKBP12.6) associates with and regulates type 2 RyRs (RyR2) in tracheal smooth muscle. FKBP12.6 binds to RyR2 but not other RyR or inositol 1,4,5-trisphosphate receptors, and FKBP12, known to bind to and modulate skeletal RyRs, does not associate with RyR2. When dialyzed into tracheal myocytes, cyclic ADP-ribose (cADPR) alters spontaneous Ca~(2+) release at lower concentrations and produces macroscopic Ca~(2+) release at higher concentrations; neurotransmitter-evoked Ca~(2+) release is also augmented by cADPR. These actions are mediated through FKBP12.6 because they are inhibited by molar excess of recombinant FKBP12.6 and are not observed in myocytes from FKBP12.6-knockout mice. We also report that force development in FKBP12.6-null mice, observed as a decrease in the concentration/tension relationship of isolated trachealis segments, is impaired. Taken together, these findings point to an important role of the FKBP12.6/RyR2 complex in stochastic (spontaneous) and receptor-mediated Ca~(2+) release in smooth muscle.
机译:ryanodine受体(RyRs)释放的细胞内Ca〜(2+)在平滑肌兴奋-收缩偶联中起重要作用,但对潜在的调节机制了解甚少。在这里,我们显示12.6 kDa(FKBP12.6)的FK506结合蛋白与气管平滑肌中的2型RyRs(RyR2)相关联并对其进行调节。 FKBP12.6与RyR2结合,但不与其他RyR或肌醇1,4,5-三磷酸酯受体结合,而已知结合并调节骨骼RyRs的FKBP12不与RyR2缔合。当渗入气管心肌细胞时,环状ADP-核糖(cADPR)在较低浓度下会改变自发Ca〜(2+)释放,并在较高浓度下产生宏观的Ca〜(2+)释放。神经递质诱发的Ca〜(2+)释放也通过cADPR增强。这些作用是通过FKBP12.6介导的,因为它们受到摩尔过量的重组FKBP12.6的抑制,并且在FKBP12.6敲除小鼠的肌细胞中未观察到。我们还报告说,FKBP12.6空小鼠中的力量发展受到损害,因为孤立气管节段的浓度/张力关系降低。综上所述,这些发现表明FKBP12.6 / RyR2复合体在平滑肌中随机(自发)和受体介导的Ca〜(2+)释放中具有重要作用。

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