Binding characteristics of the doxepin E/Z-isomers to the histamine H receptor revealed by receptor-bound ligand analysis and molecular dynamics study.

Doxepin is an antihistamine and tricyclic antidepressant that binds to the histamine H receptor (HR) with high affinity. Doxepin is an 85:15 mixture of the E- and Z-isomers. The Z-isomer is well known to be more effective than the E-isomer, whereas based on the crystal structure of the HR/doxepin complex, the hydroxyl group of Thr112 is close enough to form a hydrogen bond with the oxygen atom of the E-isomer.

Sp1-mediated downregulation of P2X4 receptor gene transcription in endothelial cells exposed to shear stress.

Endothelial purinoceptors play an important role in vascular responses to extracellular adenine nucleotides and hemodynamic forces. Here we report that P2X4 purinoceptor expression in human umbilical vein endothelial cells is transcriptionally downregulated by fluid shear stress. When human umbilical vein endothelial cells were subjected to a laminar shear stress of 15 dyn/cm(2), P2X4 mRNA levels began to decrease within 1 h and further decreased with time, reaching 60% at 24 h.

Fluid shear stress activates Ca(2+) influx into human endothelial cells via P2X4 purinoceptors.

Ca(2+) signaling plays an important role in endothelial cell (EC) responses to shear stress generated by blood flow. Our previous studies demonstrated that bovine fetal aortic ECs showed a shear stress-dependent Ca(2+) influx when exposed to flow in the presence of extracellular ATP. However, the molecular mechanisms of this process, including the ion channels responsible for the Ca(2+) response, have not been clarified.

P2X(4) receptors mediate ATP-induced calcium influx in human vascular endothelial cells.

ATP induces Ca(2+) influx across the cell membrane and activates release from intracellular Ca(2+) pools in vascular endothelial cells (ECs). Ca(2+) signaling leads to the modification of a variety of EC functions, including the production of vasoactive substances such as nitric oxide and prostacyclin. However, the molecular mechanisms for ATP-induced Ca(2+) influx in ECs have not been thoroughly clarified.