Characteristics and molecular basis of celecoxib modulation on K(v)7 potassium channels.

BACKGROUND AND PURPOSE

Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor used for the treatment of pain and inflammation. Emerging and accumulating evidence suggests that celecoxib can affect cellular targets other than COX, such as ion channels. In this study, we characterized the effects of celecoxib on K(v)7 K(+) channels and compared its effects with the well-established K(v)7 channel opener retigabine.

EXPERIMENTAL APPROACH

A perforated whole-cell patch technique was used to record K(v)7currents expressed in HEK 293 cells and M-type currents from rat superior cervical ganglion neurons.

KEY RESULTS

Celecoxib enhanced K(v)7.2-7.4, K(v)7.2/7.3 and K(v)7.3/7.5 currents but inhibited K(v)7.1 and K(v)7.1/KCNE1 currents and these effects were concentration dependent. The IC(50) value for inhibition of K(v)7.1 channels was approximately 4 µM and the EC(50) values for activation of K(v)7.2-7.4, K(v)7.2/K(v)7.3 and K(v)7.3/K(v)7.5 channels were approximately 2-5 µM. The effects of celecoxib were manifested by increasing current amplitudes, shifting the voltage-dependent activation curve in a more negative direction and slowing the deactivation of K(v)7 currents. 2,5-Dimethyl-celecoxib, a celecoxib analogue devoid of COX inhibition activity, has similar but greater effects on K(v)7currents. K(v)7.2(A235T) and K(v) 7.2(W236L) mutant channels, which have greatly attenuated responses to retigabine, showed a reversed response to celecoxib, from activation to inhibition.

CONCLUSIONS AND IMPLICATIONS

These results suggest that K(v)7 channels are targets of celecoxib action and provide new mechanistic evidence for understanding the effects of celecoxib. They also provide a new approach to developing K(v)7 modulators and for studying the structure-function relationship of K(v)7 channels.