カベオラによる血管平滑筋における興奮転写連関の制御

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  • Obligatory roles of caveolae in excitation-transcription coupling in vascular smooth muscle cells.

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<p>In smooth muscle cells (SMCs), caveolin (cav)-1, an essential component of caveolae, forms Ca2+ microdomain accumulating voltage-dependent Ca2+ channels (VDCC) and ryanodine receptors (RyR). The functional coupling between VDCC and RyR causes SMC contraction, i.e. excitation-contraction (E-C) coupling. On the other hand, Ca2+ influx through VDCC activates Ca2+/calmodulin-dependent protein kinase (CaMK), and promotes gene transcription in neurons, i.e. excitation-transcription (E-T) coupling. E-T coupling is known in SMCs, but its structural basis and physiological function are unknown. Therefore, we examined the relationships between Ca2+ microdomain formed by caveolae and E-T coupling in SMCs. When the mesenteric artery was depolarized, the phosphorylation of CREB in the nuclei of SMCs and induction of c-fos was detected. These responses were not observed in the tissue of Cav-1 KO mouse that lacks caveolae in SMCs and those in which caveolae were destroyed by methyl b cyclodextrin. The CREB phosphorylation was significantly attenuated by a CaMKK2 inhibitor STO609 and CaMK2 inhibitor KN93. Furthermore, fluorescence imaging analyses detected a direct molecular coupling between cav1 and CaMKK2. These results suggest that caveolae accumulate Ca2+ channels and CaMKK2 and cause not only E-C coupling but also E-T coupling in SMCs.</p>

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