“…The K Ca 3.1 activator 1‐EBIO or NS309 also activates K Ca 2.3 with similar potency (Coleman et al ., 2014). K Ca 2.3 shares many properties with K Ca 3.1 (Jensen et al ., 2001) and it has been implicated in endothelium‐dependent dilation (Grgic et al ., 2009).…”
SummaryEndothelial oxidative stress develops with aging and reactive oxygen species impair endothelium‐dependent relaxation (EDR) by decreasing nitric oxide (NO) availability. Endothelial KCa3.1, which contributes to EDR, is upregulated by H2O2. We investigated whether KCa3.1 upregulation compensates for diminished EDR to NO during aging‐related oxidative stress. Previous studies identified that the levels of ceramide synthase 5 (CerS5), sphingosine, and sphingosine 1‐phosphate were increased in aged wild‐type and CerS2 mice. In primary mouse aortic endothelial cells (MAECs) from aged wild‐type and CerS2 null mice, superoxide dismutase (SOD) was upregulated, and catalase and glutathione peroxidase 1 (GPX1) were downregulated, when compared to MAECs from young and age‐matched wild‐type mice. Increased H2O2 levels induced Fyn and extracellular signal‐regulated kinases (ERKs) phosphorylation and KCa3.1 upregulation. Catalase/GPX1 double knockout (catalase−/−/GPX1−/−) upregulated KCa3.1 in MAECs. NO production was decreased in aged wild‐type, CerS2 null, and catalase−/−/GPX1−/−
MAECs. However, KCa3.1 activation‐induced, NG‐nitro‐l‐arginine‐, and indomethacin‐resistant EDR was increased without a change in acetylcholine‐induced EDR in aortic rings from aged wild‐type, CerS2 null, and catalase−/−/GPX1−/− mice. CerS5 transfection or exogenous application of sphingosine or sphingosine 1‐phosphate induced similar changes in levels of the antioxidant enzymes and upregulated KCa3.1. Our findings suggest that, during aging‐related oxidative stress, SOD upregulation and downregulation of catalase and GPX1, which occur upon altering the sphingolipid composition or acyl chain length, generate H2O2 and thereby upregulate KCa3.1 expression and function via a H2O2/Fyn‐mediated pathway. Altogether, enhanced KCa3.1 activity may compensate for decreased NO signaling during vascular aging.
“…The K Ca 3.1 activator 1‐EBIO or NS309 also activates K Ca 2.3 with similar potency (Coleman et al ., 2014). K Ca 2.3 shares many properties with K Ca 3.1 (Jensen et al ., 2001) and it has been implicated in endothelium‐dependent dilation (Grgic et al ., 2009).…”
SummaryEndothelial oxidative stress develops with aging and reactive oxygen species impair endothelium‐dependent relaxation (EDR) by decreasing nitric oxide (NO) availability. Endothelial KCa3.1, which contributes to EDR, is upregulated by H2O2. We investigated whether KCa3.1 upregulation compensates for diminished EDR to NO during aging‐related oxidative stress. Previous studies identified that the levels of ceramide synthase 5 (CerS5), sphingosine, and sphingosine 1‐phosphate were increased in aged wild‐type and CerS2 mice. In primary mouse aortic endothelial cells (MAECs) from aged wild‐type and CerS2 null mice, superoxide dismutase (SOD) was upregulated, and catalase and glutathione peroxidase 1 (GPX1) were downregulated, when compared to MAECs from young and age‐matched wild‐type mice. Increased H2O2 levels induced Fyn and extracellular signal‐regulated kinases (ERKs) phosphorylation and KCa3.1 upregulation. Catalase/GPX1 double knockout (catalase−/−/GPX1−/−) upregulated KCa3.1 in MAECs. NO production was decreased in aged wild‐type, CerS2 null, and catalase−/−/GPX1−/−
MAECs. However, KCa3.1 activation‐induced, NG‐nitro‐l‐arginine‐, and indomethacin‐resistant EDR was increased without a change in acetylcholine‐induced EDR in aortic rings from aged wild‐type, CerS2 null, and catalase−/−/GPX1−/− mice. CerS5 transfection or exogenous application of sphingosine or sphingosine 1‐phosphate induced similar changes in levels of the antioxidant enzymes and upregulated KCa3.1. Our findings suggest that, during aging‐related oxidative stress, SOD upregulation and downregulation of catalase and GPX1, which occur upon altering the sphingolipid composition or acyl chain length, generate H2O2 and thereby upregulate KCa3.1 expression and function via a H2O2/Fyn‐mediated pathway. Altogether, enhanced KCa3.1 activity may compensate for decreased NO signaling during vascular aging.
“…However automated patch clamp allows for higher throughput. This technique is successfully and continuously being used for primary and secondary drug screening on a great range of ion channels, including calcium-activated potassium channel (Coleman et al, 2014).…”
“…38,39 The very close analogs, SKA-111 and SKA-121, exhibit much higher K Ca 3.1/K Ca 2 selectivity, and accentuate the primary role of the benzimidazole/benzothiazole series as being K Ca 3.1 activators. 40 In contrast to the above mentioned molecules, which show little selectivity between the K Ca 2 family members, CyPPA and its more potent congener NS13001 have fundamentally different structures and also changed selectivity profiles (Fig. 2) Mode(s) of action Basically, all KCNN activators conform with our definition of a positive gating modulator, since they act by shifting the Ca 2C -activation curve toward lower concentrations of Ca 2C in a concentration-dependent way (Fig.…”
Section: Pharmacological Modulation Of Ion Channel Gatingmentioning
confidence: 99%
“…63 This objective recently seems to have been achieved with the demonstration that the K Ca 3.1 selective SKA-121 lowers blood pressure in normotensive and hypertensive mice without affecting heart rate. 40 However, SKA-121 has a short half-life (at least in rodents) and therefore does not constitute an ideal candidate compound for development.…”
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