Transient receptor potential channels in endothelium: solving the calcium entry puzzle?

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.