Mechanism of K(v)2.1 channel inhibition by a selective COX-2 inhibitor SC-791-modification of gating.
Recent research suggests that some clinical effects of coxibs, selective inhibitors of cyclooxygenase-2 (COX-2), can be mediated via modulation of ion channels. It has been shown that clinically relevant concentrations of celecoxib can cause inhibition or augmentation of various ionic currents and alter functioning of neurons and myocytes. Independence of these effects from inhibition of cyclooxygenases raises an important question if other structurally related COX-2 inhibitors can affect ion channels in similar fashion. Here we studied effects of SC-791, a highly selective COX-2 inhibitor, on K(v)2.1 channels expressed in HEK-293 cells. SC-791 reversibly inhibited K(v)2.1 in voltage-dependent manner with stronger inhibition at negative potentials. The values of IC₅₀ were 1.8 μM and 7.2 μM for suppression of peak current at -20 and +40 mV, respectively. The current was reduced via acceleration of inactivation, hyperpolarizing shift in the half-inactivation potential and a large depolarizing shift in the half-activation potential. In addition, SC-791 accelerated all other aspects of K(v)2.1 kinetics: activation, deactivation and recovery from inactivation. Our results show that SC-791 modified K(v)2.1 gating, but, unlike celecoxib, did not induce channel block. These findings help to understand the mechanisms of unanticipated action of COX-2 inhibitors on voltage-activated potassium channels and their physiological implications.
Frolov
Roman V
RV
Department of Pharmacology and Toxicology, State University of New York at Buffalo, Buffalo, NY 14214, USA. rvfrolov@gmail.com
Ignatova
Irina I
II
Singh
Satpal
S
D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D007555:Isoxazoles / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D051669:Shab Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*
D052246:Cyclooxygenase 2 Inhibitors; D007555:Isoxazoles; C553330:SC 791; D051669:Shab Potassium Channels; D013449:Sulfonamides