title: Caveolar remodeling is a critical mechanotransduction mechanism of the stretch-induced L-type Ca2+channel activation in vascular myocytes.
abstract: Activation of L-type voltage-dependent Ca2+channels (VDCCL) by membrane stretch contributes to many biological responses such as myogenic contraction of arteries. However, mechanism for the stretch-induced VDCCLactivation is unclear. In this study, we examined the hypothesis that caveolar remodeling and its related signaling cascade contribute to the stretch-induced activation of VDCCLin rat mesenteric arterial smooth muscle cells. The VDCCLcurrents were recorded with nystatin-perforated or with conventional whole-cell patch-clamp technique. Hypotonic (~230 mOsm) swelling-induced membrane stretch reversibly increased the VDCCLcurrents. 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 VDCCLcurrents. Moreover, subsequent hypotonic swelling after MβCD treatment failed to increase the VDCCLcurrents 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 VDCCLcurrents. Knockdown of Cav-1 by small interfering RNA blocked both the VDCCLcurrent facilitation by stretch and the related phosphorylation of JNK. Taken together, the results suggest that membrane stretch is transduced to the facilitation of VDCCLcurrents via caveolar structure-dependent tyrosine phosphorylation of Cav-1 and subsequent activation of JNK in rat mesenteric arterial myocytes.
authors.affiliation: Department of Emergency Medical Services, Eulji University, Seongnam, Gyeonggi-do, 461-713, South Korea.
authors.forename: Sang Woong
authors.initials: SW
authors.lastname: Park
authors.affiliation: Department of Physiology, KU Open Innovation Center, Research Institute of Medical Science, Konkuk University School of Medicine, Chungju, Chungbuk, 380-701, South Korea.
authors.forename: Kyung Chul
authors.initials: KC
authors.lastname: Shin
authors.affiliation: Department of Physiology, KU Open Innovation Center, Research Institute of Medical Science, Konkuk University School of Medicine, Chungju, Chungbuk, 380-701, South Korea.
authors.forename: Hyun Ji
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Department of Emergency Medical Services, Eulji University, Seongnam, Gyeonggi-do, 461-713, South Korea.
authors.forename: Soon-Kyu
authors.initials: SK
authors.lastname: Yoou
authors.affiliation: Colleage of Veterinary Medicine, Department of Biomedical Science & Technology (DBST), Konkuk University, Seoul, 143-701, South Korea.
authors.forename: Jin-Yeon
authors.initials: JY
authors.lastname: Park
authors.affiliation: Colleage of Veterinary Medicine, Department of Biomedical Science & Technology (DBST), Konkuk University, Seoul, 143-701, South Korea.
authors.forename: Young-Sun
authors.initials: YS
authors.lastname: Kang
authors.affiliation: Division of Sport Science, College of Science and Technology, Konkuk University, Chungju, Chungbuk, 380-701, South Korea.
authors.forename: Dong Jun
authors.initials: DJ
authors.lastname: Sung
authors.affiliation: Department of Physiology, KU Open Innovation Center, Research Institute of Medical Science, Konkuk University School of Medicine, Chungju, Chungbuk, 380-701, South Korea.
authors.forename: Jae Gon
authors.initials: JG
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Research Institute of Medical Science, Konkuk University School of Medicine, Chungju, Chungbuk, 380-701, South Korea.
authors.forename: Seung Hwa
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Physiology, KU Open Innovation Center, Research Institute of Medical Science, Konkuk University School of Medicine, Chungju, Chungbuk, 380-701, South Korea.
authors.forename: BoKyung
authors.initials: B
authors.lastname: Kim
authors.affiliation: Department of Physiology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, South Korea.
authors.forename: Hana
authors.initials: H
authors.lastname: Cho
authors.affiliation: Department of Physiology, KU Open Innovation Center, Research Institute of Medical Science, Konkuk University School of Medicine, Chungju, Chungbuk, 380-701, South Korea. ymbae30@kku.ac.kr.
authors.forename: Young Min
authors.initials: YM
authors.lastname: Bae
mesh_terms: D000200:Action Potentials; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D021941:Caveolae / Q000378:metabolism* / Q000648:ultrastructure; D051242:Caveolin 1 / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000172:deficiency; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D040542:Mechanotransduction, Cellular; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D009997:Osmotic Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D015220:Calcium Channels; D051242:Caveolin 1; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D002784:Cholesterol; D048670:MAP Kinase Kinase 4
keywords: C-Jun N-terminal kinase; Caveolae; Caveolin; Stretch; Voltage-dependent calcium channel