LIMK2 is required for membrane cytoskeleton reorganization of contracting airway smooth muscle.
Airway smooth muscle (ASM) has developed a mechanical adaption mechanism by which it transduces force and responds to environmental forces, which is essential for periodic breathing. Cytoskeletal reorganization has been implicated in this process, but the regulatory mechanism remains to be determined. We here observe that ASM abundantly expresses cytoskeleton regulators Limk1 and Limk2, and their expression levels are further upregulated in chronic obstructive pulmonary disease (COPD) animals. By establishing mouse lines with deletions of Limk1 or Limk2, we analyse the length-sensitive contraction, F/G-actin dynamics, and F-actin pool of mutant ASM cells. As LIMK1 phosphorylation does not respond to the contractile stimulation, LIMK1-deficient ASM develops normal maximal force, while LIMK2 or LIMK1/LIMK2 deficient ASMs show approximately 30% inhibition. LIMK2 deletion causes a significant decrease in cofilin phosphorylation along with a reduced F/G-actin ratio. As LIMK2 functions independently of cross-bridge movement, this observation indicates that LIMK2 is necessary for F-actin dynamics and hence force transduction. Moreover, LIMK2-deficient ASMs display abolishes stretching-induced suppression of 5-hydroxytryptamine (5-HT) but not acetylcholine-evoks force, which is due to the differential contraction mechanisms adopted by the agonists. We propose that LIMK2-mediated cofilin phosphorylation is required for membrane cytoskeleton reorganization that is necessary for ASM mechanical adaption including the 5-HT-evoked length-sensitive effect.
['Li|Yeqiong|Y|', 'Zhou|Yuwei|Y|', 'Wang|Pei|P|', 'Tao|Tao|T|', 'Wei|Lisha|L|', 'Wang|Ye|Y|', 'Wang|Wei|W|', 'Zheng|Yanyan|Y|', 'Jiang|Zhihui|Z|', 'Qiu|Tiantian|T|', 'Zhao|Wei|W|', 'Sun|Jie|J|', 'Chen|Xin|X|', 'Zhang|Xue-Na|XN|', 'Zhu|Min-Sheng|MS|']
Cytoskeleton Smooth muscle Cofilin LIM kinases Length sensitive effect