The nature and molecular determinants of block of the hERG potassium channel by Celecoxib, a selective COX-2 inhibitor
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Pharmacological blockade of the Human ether-a-go-go related gene (hERG) potassium channel is commonly linked with acquired long QT syndrome and associated proarrhythmia. The objective of this study was twofold. First, to characterize the inhibitory action of celecoxib on the hERG potassium channel at physiological temperature. This included an assessment of the concentration, state and voltage dependence of hERG channel blockade. Furthermore, the study aimed to determine the mechanism of action underlying the inhibition of the hERG channel by celecoxib. hERG potassium currents (IhERG) were recorded at 22°C and 37°C, using the whole-cell patch-clamp technique, from a mammalian cell line (Human Embryonic Kidney 293) either continuously expressing wild-type hERG channels or transiently expressing mutant hERG cDNAs (Y652A or F656A) in the presence (treatment) or absence (control) of celecoxib. The data suggested that celecoxib, a non-steroidal anti-inflammatory drug prescribed for rheumatoid arthritis, osteoarthritis and acute pain, inhibited the hERG potassium current in a reversible concentration dependent manner with a half maximal inhibitory concentration (IC50) of 6.1micro molar at the physiological temperature of 37°C. An assessment of the state preference of the channel blockade indicated a lack of preference for both the open and the closed states of the channel. In addition, the blockade showed voltage dependence with celecoxib inducing a 12mV leftward shift in the voltage dependent activation of IhERG. Mutant studies, wherein key amino acid residues were mutated to reveal their role in drug block, indicated that the blockade of the channel was not significantly dependent on the S6 helix amino acids F656 or Y652, which are known to play a critical role in the blockade of hERG by other drugs. Taken together the study suggests that celecoxib's action on hERG involves a mechanism that is distinct from that previously described for other hERG channel blockers. In addition it indicates the possibility of a potentially novel drug binding site involving residues other than the classic S6 domain aromatic residues, Y652 and F656.