Nilius Bernd, Droogmans Guy, Wondergem Robert
Department of Physiology, Campus Gasthuisberg O&N, KU Leuven, Leuven, Belgium.
Endothelium. 2003;10(1):5-15. doi: 10.1080/10623320303356.
Many endothelial cell (EC) functions depend on influx of extracellular Ca2+, which is triggered by a variety of mechanical and chemical signals. Here, we discuss possible pathways for this Ca2+ entry. The superfamily of cation channels derived from the "transient receptor potential" (TRP) channels is introduced. Several members of this family are expressed in ECs, and they provide pathways for Ca2+ entry. All TRP subfamilies may contribute to the Ca2+ entry channels or to the regulation of Ca2+ entry in EC. Members of Ca2+ entry channels in endothelium probably belong to the canonical TRP subfamily, TRPC. All TRPC1-6 have been discussed as Ca2+ entry channels that might be store-operated and/or receptor-operated. More importantly, knockout models of TRPC4 have proven that this channel is functionally involved in the regulation of endothelial-dependent vasorelaxation and in the control of EC barrier function. TRPC1 might be an important candidate for involvement of endothelial growth factors. TRPC3 is unequivocally important for a sustained EC Ca2+ entry. ECs express different patterns of TRPCs, which may increase the variability of TRPC channel function by formation of different multiheteromers. Among the two other TRP subfamilies, TRPMV and TRPM, at least TRPV4 and TRPM4 are EC channels. TRPV4 is a Ca2+ entry channel that is activated by an increase in cell volume, which might be involved in mechano-sensing, by an increase in temperature, and perhaps by ligand-activation. TRPM4 is a nonselective cation channel, which is not Ca2+ permeable. It is probably modulated by NO and might be essential for regulating the inward driving force for Ca2+ entry. Possible modes of TRP channel regulation are described, involving (a) activation via the phospholipase (PL)Cbeta and PLC-gamma pathways; (b) activation by lipids (diacylglycerol [DAG], arachidonic acid); (c) Ca2+ depletion of Ca2+ stores in the endoplasmic reticulum; (d) shear stress; and (e) radicals.
许多内皮细胞（EC）功能依赖于细胞外Ca2+的内流，这是由多种机械和化学信号触发的。在此，我们讨论这种Ca2+内流的可能途径。介绍了源自“瞬时受体电位”（TRP）通道的阳离子通道超家族。该家族的几个成员在内皮细胞中表达，它们为Ca2+内流提供途径。所有TRP亚家族可能都有助于Ca2+内流通道或内皮细胞中Ca2+内流的调节。内皮细胞中Ca2+内流通道的成员可能属于典型的TRP亚家族，即TRPC。所有TRPC1-6都被讨论为可能是储存操纵和/或受体操纵的Ca2+内流通道。更重要的是，TRPC4基因敲除模型已证明该通道在功能上参与内皮依赖性血管舒张的调节以及EC屏障功能的控制。TRPC1可能是内皮生长因子参与的重要候选者。TRPC3对于持续的内皮细胞Ca2+内流无疑很重要。内皮细胞表达不同模式的TRPC，这可能通过形成不同的多聚体增加TRPC通道功能的变异性。在另外两个TRP亚家族TRPMV和TRPM中，至少TRPV4和TRPM4是内皮细胞通道。TRPV4是一种Ca2+内流通道，可被细胞体积增加激活，这可能参与机械传感，也可被温度升高激活，或许还可被配体激活。TRPM4是一种非选择性阳离子通道，不具有Ca2+通透性。它可能受一氧化氮调节，可能对调节Ca2+内流的内向驱动力至关重要。描述了TRP通道调节的可能模式，包括（a）通过磷脂酶（PL）Cβ和PLC-γ途径激活；（b）被脂质（二酰基甘油[DAG]、花生四烯酸）激活；（c）内质网中Ca2+储存的Ca2+耗竭；（d）剪切应力；以及（e）自由基。
