血管受容体作動性CaチャネルTRPC6の受容体・機械刺激による相乗活性化機構

抄録

TRPC6 is ubiquitously expressed in vascular smooth muscle cells (VSMCs) and implicated in the regulation of vascular tone and remodeling. In several different types of VSMCs, stimulation of phospholipase C-liked receptors can activate this channel via generation of diacylglycerol. In other VSMCs showing prominent blood flow autoregulation, elevated intravascular pressure itself can activate TRPC6 channel eliciting a reflex vasoconstriction (myogenic response). However, our recent investigations demonstrate that TRPC6 channel can be activated synergistically by receptor stimulation and mechanical forces in both heterologous expression system and native VSMCs. Application of mechanical forces (e.g. hypotonic or shear stresses), albeit not effective by themselves, induced large cationic currents, when subthreshold receptor activation or weak direct activation of G-protein by GTPγS preceded, and inclusion of agonist in the patch pipette greatly lowered the threshold of negative pressure to elicit single channel activities. Importantly, this synergism was not affected by a mechanosensitive cation channel blocker GsMTx but was strongly attenuated by specific inhibition of ω-hydroxylation which generates 20-hydroxyeicosatetraenoic acid, a reportedly potent vasoconstrictive lipid messenger. Consistent with these results, video-microscopic diameter measurement of cannulated mesenteric artery revealed that this mechanism may operate in sensitized myogenic response to intravascular pressure increase under weak receptor stimulation. [J Physiol Sci. 2008;58 Suppl:S9]