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M3 muscarinic acetylcholine receptor dysfunction inhibits Rac1 activity and disrupts VE-cadherin/β-catenin and actin cytoskeleton interaction

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The objective was to investigate whether M3 muscarinic acetylcholine receptor (mAChR) dysfunction disrupts the linkage between the vascular endothelial (VE)-cadherin in the adherens junctional complex and the actin-based cytoskeleton, increasing vascular permeability in atherosclerosis. Western blotting revealed that a selective M3 receptor antagonist, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), and M3 receptor siRNA decrease VE-cadherin and β-catenin in Triton X-100–insoluble fractions, indicating that M3 receptor inhibition weakens the linkage between the VE-cadherin/β-catenin complex and the actin cytoskeleton. Co-immunoprecipitation assays showed that M3 receptor inhibition reduces Rac1 activity and the association of IQ motif-containing GTPase-activating protein 1 (IQGAP1) with Ras-related C3 botulinum toxin substrate 1 (Rac1), while increasing the interaction between IQGAP1 and β-catenin. Using IQGAP1 siRNA, we found that IQGAP1 is required for stable interaction between VE-cadherin/β-catenin and the actin cytoskeleton in quiescent endothelial cells; IQGAP1 siRNA augments the M3 receptor inhibition-induced dissociation between them. Moreover, S-nitroso-N-acetylpenicillamine (SNAP), a nitric oxide (NO) donor, attenuates this disassociation and Rac1 activity inhibition. The M3 receptor facilitates interaction of the VE-cadherin–based adherens junctional complex and the actin-based cytoskeleton by maintaining Rac1 activity, which regulates the interaction between IQGAP1/Rac1 and IQGAP1/β-catenin, and may contribute to endothelial barrier function under physiological conditions.
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Keywords: IQGAP1; M3 mAChR; Rac1; VE-cadherin; VE-cadhérine; ß-caténine; β-catenin

Document Type: Research Article

Affiliations: 1: Department of Cardiovascular Surgery, Xiehe Hospital, Huazhong University of Science and Technology, Wuhan, 430022, China. 2: Department of Pediatrics, First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China. 3: Department of Cardiovascular Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.

Publication date: January 1, 2014

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