IndraLab

"XREF_BIBR It is a heterogeneous disease caused by pathogenic variants in at least 3 different potassium channel genes KCNH2, KCNQ1, and KCNJ2 and the cardiac chloride-bicarbonate exchanger gene SLC4A3."

"These defects in potassium channel genes cause LQTS by reducing the repolarizing current carried by the specific potassium channel they encode, i.e. the I Ks ( KCNQ1 and KCNE1 ) and the I Kr channel ([MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

"C unbound plasma concentration E maximal hERG mediated QT prolongation f fraction unbound hERGhuman ether-a-go-go-related gene I repolarizing potassium current mediated by the delayed rectifier potassium channel K receptor affinity Lligand LRligand and receptor complex (receptor occupancy) LR ligand and receptor complex concentration leading to half-maximal system effect NONMEMnonlinear mixed effect modeling QTcQT interval corrected for heart rate and circadian variation DeltaQTcdrug induced QTc prolongation R receptor density gammaslope (sigmodicity) of transducer function DeltaOFVdifference in NONMEM objective function value tautransducer ratio f relative transducer ratio Introduction."

"Approximately 90% of LQT cases are linked to mutations in the KCNQ1 (type 1 LQT; LQT1), KCNH2 (type 2 LQT; LQT2), and SCN5A (type 3 LQT; LQT3) genes, and about 45% of these cases are caused by changes in the potassium channels KCNQ1 and KCNH2 (5, 6)."

"Because most LQTS associated drugs interact with the HERG potassium channel (the product of KCNH2), we asked if this was the only target contributing to the observed enrichment."

"XREF_BIBR - XREF_BIBR Among these agents, astemizole and terfenadine are no longer in use because of cardio-toxicity caused by their potassium channel blocker activity (hERG encoded by KCNH2), which may lead to fatal cardiac arrhythmia."

"QTc prolongation is a manifestation of a delayed ventricular repolarization that occurs as certain medications block the hERG potassium channel (product of the gene KCNH2), and as a result, block the delayed rectifier potassium current (IKr) [39]."

"In other words, an increase in the hERG current by matrine is caused by the promotion of hERG potassium channel activation."

"Inhibition of the human cardiac potassium channel hERG is a liability of this series and reducing hERG inhibition has been the focus of recent lead optimization efforts [ 34 ]."

"Most medications that prolong the QT interval, including aminoquinolines, act by binding to and inhibiting the potassium channel protein product of the gene KCNH2 (also known as hERG), thereby blocking the rapid component of the delayed rectifier potassium current (I Kr)."

"KIEHN J, KARLE C, THOMAS D et al.: HERG potassium channel activation is shifted by phorbol esters via protein kinase A-dependent pathways."

"Such unique role of hERG potassium channel was also supported by the evidence that the effect of the toxin BmKKx2 on cell differentiation was nullified in hERG deficient cell lines."

"In particular, the correction of the trafficking of KCNH2 (LQTS2) potassium channel through intracellular mechanisms restored hERG currents and reduced arrhythmia in LQTS2 patient derived cardiomyocytes, also documenting the usefulness of iPSC-cardiomyocytes in LQTS2 modeling and drug testing."