Smooth muscle of telokin-deficient mice exhibits increased sensitivity to Ca2+ and decreased cGMP-induced relaxation
Smooth muscle of telokin-deficient mice exhibits increased sensitivity to Ca2+ and decreased cGMP-induced relaxation
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DOI：
10.1073/pnas.0508566103
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发表时间：
2006-02-14
影响因子：
11.1
通讯作者：
Somlyo, AV
中科院分区：
文献类型：
--
作者：
Khromov, AS;Wang, H;Somlyo, AV
环核苷酸可以松弛平滑肌而不改变[Ca 2 +]（i），这是一种称为Ca 2+脱敏的现象，有助于血管舒张、胃肠道运动和气道阻力。telokin，17 kDa的平滑肌特异性蛋白和目标环核苷酸诱导的钙脱敏的生理重要性，在telokin基因敲除小鼠繁殖的同类背景。与野生型相比，不含端粒蛋白的回肠平滑肌匀浆表现出肌球蛋白轻链磷酸酶（MLCP）活性降低约30%，这反映在Ca 2+力关系的显著漂移（pCa 6.3时高达2倍），伴随着肌球蛋白轻链磷酸化的增加。在telokin WT和敲除（KO）平滑肌中，Ca 2+力关系没有差异，推测反映了主动脉与回肠平滑肌中telokin含量通常约低5倍。8-Br-cGMP对telokin KO肠平滑肌收缩力的Ca ~（2+）脱敏作用减弱50%。在存在50 μ M 8-Br-cGMP的情况下，反映MLCP活性的力松弛速率在telokin KO与WT回肠中也显著减慢，并且被重组telokin挽救。telokin KO平滑肌中的正常粗丝表明telokin对于丝的形成或稳定性不是必需的。结果表明，telokin的主要作用是通过增加MLCP活性来调节力，并且在富含telokin的平滑肌组织中通过cGMP的磷酸化进一步增强这种作用。
Cyclic nucleotides can relax smooth muscle without a change in [Ca2+](i), a phenomenon termed Ca2+ desensitization, contributing to vasodilation, gastrointestinal motility, and airway resistance. The physiological importance of telokin, a 17-kDa smooth muscle-specific protein and target for cyclic nucleotide-induced Ca2+ desensitization, was determined in telokin null mice bred to a congenic background. Telokin null ileal smooth muscle homogenates compared to wild type exhibited an approximate to 30% decrease in myosin light-chain phosphatase (MLCP) activity, which was reflected in a significant leftward shift (up to 2-fold at pCa 6.3) of the Ca2+ force relationship accompanied by an increase in myosin light-chain phosphorylation. No difference in the Ca2+ force relationship occurred in telokin WT and knockout (KO) aortas, presumably reflecting the normally approximate to 5-fold lower telokin content in aorta vs. ileum smooth muscle. Ca2+ desensitization of contractile force by 8-Br-cGMP was attenuated by 50% in telokin KO intestinal smooth muscle. The rate of force relaxation reflecting MLCP activity, in the presence of 50 mu M 8-Br-cGMP, was also significantly slowed in telokin KO vs. WT ileum and was rescued by recombinant telokin. Normal thick filaments in telokin KO smooth muscles indicate that telokin is not required for filament formation or stability. Results indicate that a primary role of telokin is to modulate force through increasing MLCP activity and that this effect is further potentiated through phosphorylation by cGMP in telokin-rich smooth tissues.