TRPC6型
小窝蛋白1
小窝
酪氨酸磷酸化
磷酸化
细胞生物学
内分泌学
内科学
生物
化学
受体
瞬时受体电位通道
信号转导
生物化学
医学
作者
Tian Jiang,Rudi Samapati,Sergej Klassen,Disi Lei,Lasti Erfinanda,Vera Jankowski,Szandor Simmons,Jun Yin,Christoph Arenz,Alexander Dietrich,Thomas Gudermann,Dieter Adam,Michael Schaefer,Joachim Jankowski,Veit Flockerzi,Rolf M. Nüsing,Stefan Uhlig,Wolfgang M. Kuebler
出处
期刊:The European respiratory journal
[European Respiratory Society]
日期:2022-04-21
卷期号:60 (4): 2102635-2102635
被引量:3
标识
DOI:10.1183/13993003.02635-2021
摘要
Background Prostaglandin E 2 (PGE 2 ) increases pulmonary vascular permeability by activation of the PGE 2 receptor 3 (EP 3 ), which may explain adverse pulmonary effects of the EP 1 /EP 3 receptor agonist sulprostone in patients. In addition, PGE 2 contributes to pulmonary oedema in response to platelet-activating factor (PAF). PAF increases endothelial permeability by recruiting the cation channel transient receptor potential canonical 6 (TRPC6) to endothelial caveolae via acid sphingomyelinase (ASMase). Yet, the roles of PGE 2 and EP 3 in this pathway are unknown. We hypothesised that EP 3 receptor activation may increase pulmonary vascular permeability by activation of TRPC6, and thus, synergise with ASMase-mediated TRPC6 recruitment in PAF-induced lung oedema. Methods In isolated lungs, we measured increases in endothelial calcium (ΔCa 2+ ) or lung weight (Δweight), and endothelial caveolar TRPC6 abundance as well as phosphorylation. Results PAF-induced ΔCa 2+ and Δweight were attenuated in EP 3 -deficient mice. Sulprostone replicated PAF-induced ΔCa 2+ and Δweight which were blocked by pharmacological/genetic inhibition of TRPC6, ASMase or Src-family kinases (SrcFK). PAF, but not sulprostone, increased TRPC6 abundance in endothelial caveolae. Immunoprecipitation revealed PAF- and sulprostone-induced tyrosine-phosphorylation of TRPC6 that was prevented by inhibition of phospholipase C (PLC) or SrcFK. PLC inhibition also blocked sulprostone-induced ΔCa 2+ and Δweight, as did inhibition of SrcFK or inhibitory G-protein (G i ) signalling. Conclusions EP 3 activation triggers pulmonary oedema via G i -dependent activation of PLC and subsequent SrcFK-dependent tyrosine phosphorylation of TRPC6. In PAF-induced lung oedema, this TRPC6 activation coincides with ASMase-dependent caveolar recruitment of TRPC6, resulting in rapid endothelial Ca 2+ influx and barrier failure.
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