Caveolar remodeling is a critical mechanotransduction mechanism of the stretch-induced L-type Ca2+ channel activation in vascular myocytes

• Published in: Pflügers Archiv Vol. 469; no. 5-6; pp. 829 - 842
• Main Authors: Park, Sang Woong, Shin, Kyung Chul, Park, Hyun Ji, Yoou, Soon-Kyu, Park, Jin-Yeon, Kang, Young-Sun, Sung, Dong Jun, Kim, Jae Gon, Park, Seung Hwa, Kim, BoKyung, Cho, Hana, Bae, Young Min
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2017
• Subjects: Biomedical and Life Sciences; Biomedicine; Cell Biology; Human Physiology; Molecular Medicine; Neurosciences; Receptors; Signaling and Cell Physiology; Stretch; Caveolae; Voltage-dependent calcium channel; C-Jun N-terminal kinase; Caveolin
• ISSN: 0031-6768; 1432-2013
• DOI: 10.1007/s00424-017-1957-3

Activation of L-type voltage-dependent Ca 2+ channels (VDCC L ) by membrane stretch contributes to many biological responses such as myogenic contraction of arteries. However, mechanism for the stretch-induced VDCC L activation is unclear. In this study, we examined the hypothesis that caveolar remodeling and its related signaling cascade contribute to the stretch-induced activation of VDCC L in rat mesenteric arterial smooth muscle cells. The VDCC L currents were recorded with nystatin-perforated or with conventional whole-cell patch-clamp technique. Hypotonic (~230 mOsm) swelling-induced membrane stretch reversibly increased the VDCC L currents. Electron microscope and confocal imaging analysis revealed that both hypotonic swelling and cholesterol depletion by methyl-β-cychlodextrin (MβCD) similarly disrupted the caveolae structure and translocated caveolin-1 (Cav-1) from membrane to cytosolic space. Accordingly, MβCD also increased VDCC L currents. Moreover, subsequent hypotonic swelling after MβCD treatment failed to increase the VDCC L currents further. Western blotting experiments revealed that hypotonic swelling phosphorylated Cav-1 and JNK. Inhibitors of tyrosine kinases (genistein) and JNK (SP00125) prevented the swelling-induced facilitation of VDCC L currents. Knockdown of Cav-1 by small interfering RNA blocked both the VDCC L current facilitation by stretch and the related phosphorylation of JNK. Taken together, the results suggest that membrane stretch is transduced to the facilitation of VDCC L currents via caveolar structure-dependent tyrosine phosphorylation of Cav-1 and subsequent activation of JNK in rat mesenteric arterial myocytes.