Mechanisms of Kv2.1 channel inhibition by celecoxib--modification of gating and channel block.

BACKGROUND AND PURPOSE

Selective cyclooxygenase-2 (COX-2) inhibitors such as rofecoxib (Vioxx) and celecoxib (Celebrex) were developed as NSAIDs with reduced gastric side effects. Celecoxib has now been shown to affect cellular physiology via an unexpected, COX-independent, pathway - by inhibiting K(v)2.1 and other ion channels. In this study, we investigated the mechanism of the action of celecoxib on K(v)2.1 channels.

EXPERIMENTAL APPROACH

The mode of action of celecoxib on rat K(v)2.1 channels was studied by whole-cell patch-clamping to record currents from channels expressed in HEK-293 cells.

KEY RESULTS

Celecoxib reduced current through K(v)2.1 channels when applied from the extracellular side. At low concentrations (<or=3 microM), celecoxib accelerated kinetics of activation, deactivation and inactivation. Recovery of rat K(v)2.1 channels from inactivation could be characterized by two components, with celecoxib selectively accelerating the slow component of recovery at <or=10 microM. At >3 microM, celecoxib led to closed-channel block with relative slowing of activation. At 30 microM, it additionally induced open-channel block that manifested in use-dependent inhibition and slower recovery from inactivation.

CONCLUSIONS AND IMPLICATIONS

Celecoxib reduced current through K(v)2.1 channels by modifying gating and inducing closed- and open-channel block, with the three effects manifesting at different concentrations. These data will help to elucidate the mechanisms of action of this widely prescribed drug on ion channels and those underlying its neurological, cardiovascular and other effects.