K+ channels inhibition

Transduction mechanism Inhibition of adenylyl cyclase stimulation of tyrosine phosphatase activity stimulation of MAP kinase activity activation of ERK inhibition of Ca2+ channel activation stimulation of Na+/H+ exchanger stimulation of AM PA/kainate glutamate channels Inhibition of forskol in-stimulated adenylyl cyclase activation of phos-phoinositide metabolism stimulation of tyrosine phosphatase activity inhibition of Ca2+ channel activation activation of K+ channel inhibition of AM PA/ kainate glutamate channels inhibition of MAP kinase activity inhibition of ERK stimulation of SHP-1 and SHP-2 Inhibition of adenylyl cyclase stimulation of phosphoinositide metabolism stimulation of tyrosine phosphatase activation of K+ channel inhibi-tion/stimulation of MAP kinase activity induction of p53 and Bax Inhibition of adenylyl cyclase stimulation of MAP kinase stimulation of p38 activation of tyrosine phosphatase stimulation of K+ channels and phospholipase A2 Inhibition of adenylyl cyclase activation/ inhibition of phosphoinositide metabolism inhibition of Ca2+ influx activation of K+ channels inhibition of MAP kinase stimulation of tyrosine phosphatase... 

Inhibition of adenylyl cyclase opening of K+ channels Inhibition of adenylyl cyclase... 

However, when compound 15 was tested for h E RG K+ channel inhibition, a basic cardiovascular safety indicator related to the QT prolongation syndrome [32], and linked to ventricular fibrillation and sudden death [33], we were unpleasantly surprised. Although the lead compound 1 exhibited very weak binding to the hERG K+ channel (IC50 > 5000 nM), the optimized compound 15 was afairly potent hERG blocker with an inhibition concentration IC50 of 300 nM (in patch-clamp assay). 

Upon activation all three (X2AR subtypes are coupled to their intracellular messenger systems via heterotrimeric G /0 proteins (Figure 2). Intracellular consequences of 0C2AR activation are reduced cAMP levels due to inhibition of adenylyl cyclase, opening of GIRK K+ channels, inhibition of neuronal Ca2+ channels, and... 

Renaudo A, Watry V, Chassot AA, Ponzio G, Ehrenfeld J, Soriani O (2004) Inhibition of tumor cell proliferation by sigma ligands is associated with K+ Channel inhibition and p27kipl accumulation. J Pharmacol Exp Ther 311 1105-1114... 

Wang ZH, Shen B, Yao HL, Jia YC, Ren J, Feng YJ, Wang YZ (2007) Blockage of intermediate-conductance-Ca2+-activated K+ channels inhibits progression of human endometrial cancer. Oncogene 26 5107-5114... 

Understanding the mechanisms underlying regulation of K" " channel activity by acute reduction in environmental O2 has been hampered by the fact that in 02-sensing tissues these channels often represent only one of a whole gamut of native, expressed K channel proteins, as well as other ion channel types. Furthermore, pharmacological and/or biophysical dissection of specific K" " channel types is not always possible. Clearly, to study in detail the precise mode of hypoxic K" " channel inhibition, it would be desirable to record activity from a pure... 

In both rodent NEBs (7,9) and H146 cells (11,83,84), hypoxia causes K+-channel inhibition and cell depolarization (Fig. 7) and the key upstream event in airway O2 sensing is modulation of cellular redox potential via substrate-limited generation of reactive oxygen species (ROS) by NADPH oxidase (72,75,83,84). The NADPH oxidase model predicts that the tonie and sequential generation of superoxide and... 

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