Redox control of ion channel activity in vascular endothelial cells by glutathione.
Oxidized glutathione (GSSG) is endogenously formed within vascular endothelial cells. The bioactivity of GSSG results in the oxidation of protein thiol groups, leading to changes in protein structure-function relationships. When ion channel protein thiols are the target of oxidation by GSSG, important changes in channel conductance, activity, and gating occur. In this review, we focus on two endothelial cell ion channels, the activities of which influence vascular cell signaling and the nitric oxide signaling pathway. The first channel is the GSSG-operated cation channel that depolarizes the endothelial cell, leading to inhibition of capacitative Ca2+ entry. The second channel is the inositol 1,4,5-triphosphate (IP3)-operated Ca2+ channel that is responsible for the agonist-stimulated release of Ca2+ from IP3-sensitive endoplasmic reticulum. GSSG acts to deplete IP3-sensitive Ca2+ stores, thereby attenuating the intracellular Ca2+ response to agonist stimulation. Together, these effects indicate that glutathione, which is formed endogenously within the cell, is a key physiological modulator of endothelial cell signaling.
Elliott
S J
SJ
Department of Pediatrics and Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee 53226, USA. elliott@mcw.edu
Koliwad
S K
SK
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007473:Ion Channels / Q000378:metabolism*; D010084:Oxidation-Reduction; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism
D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007473:Ion Channels; D018160:Receptors, Cytoplasmic and Nuclear; D013438:Sulfhydryl Compounds; D015544:Inositol 1,4,5-Trisphosphate; D005978:Glutathione; D002118:Calcium; D019803:Glutathione Disulfide