A molecular complex of Ca v 1.2/CaMKK2/CaMK1a in caveolae is responsible for vascular remodeling via excitation–transcription coupling

• DOI: 10.1073/pnas.2117435119
• Publication Date: 2022-04-13T09:53:06Z
• Authors: Yoshiaki Suzuki; Takumi Ozawa; Tomo Kurata; Nanami Nakajima; Gerald W. Zamponi; Wayne R. Giles; Yuji Imaizumi; Hisao Yamamura
• Keywords: Transcription

Elevation of intracellular Ca2+ concentration ([Ca2+]i) activates Ca2+/calmodulin-dependent kinases (CaMK) and promotes gene transcription. This signaling pathway is referred to as excitation–transcription (E-T) coupling. Although vascular myocytes can exhibit E-T coupling, the molecular mechanisms physiological/pathological roles are unknown. Multiscale analysis spanning from single molecules whole organisms has revealed essential steps in mouse myocyte Upon a depolarizing stimulus, influx through Cav1.2 voltage-dependent channels CaMKK2 CaMK1a, resulting intranuclear CREB phosphorylation. Within caveolae, formation complex Cav1.2/CaMKK2/CaMK1a promoted myocytes. Live imaging using genetically encoded indicator direct activation by localized caveolae. CaMK1a phosphorylated at caveolae translocated nucleus upon membrane depolarization. In addition, sustained depolarization mesenteric artery preparation induced genes related chemotaxis, leukocyte adhesion, inflammation, these changes were reversed inhibitors Cav1.2, CaMKK2, CaMK, or disruption context pathophysiology, when was loaded high pressure vivo, we observed phosphorylation myocytes, macrophage accumulation adventitia, an increase thickness cross-sectional area tunica media. These reduced caveolin1-knockout mice treated with inhibitor STO609. summary, coupling depends on this converts [Ca2+]i into ultimately leads media remodeling for adaptation increased circumferential stretch.