K(v)LQT channels are inhibited by the K+ channel blocker 293B*

Previous data have indicated that the chromanol 293B blocks a cAMP activated K+ conductance in the colonic crypt, a K+ conductance in pig cardiac myocytes and the K+ conductance induced by IsK protein expression in Xenopus oocytes. We have also shown that cAMP-activated cystic fibrosis transmembrane conductance regulator (CFTR) up-regulates, apart from the typical Cl- current, a 293B- inhibitable K+ current. Very recently it has been shown that the IsK protein interacts with K(v)LQT subunits to produce a K+ channel. These data have prompted us to ask the following questions: Is the 293B-inhibitable current in oocytes expressing CFTR and activated by cAMP caused by an endogenous Xenopus K(v)LQT (XK(v)LQT), and is mouse K(v)LQT (mK(v)LQT) expressed in oocytes inhibited by 293B? Antisense and sense probes for XK(v)LQT were coinjected with CFTR cRNA into oocytes. After 3-4 days the oocytes were examined by two electrode voltage clamp. It was found that in control oocytes expressing CFTR and stimulated by isobutylmethylxanthine (IBMX, 1 mmol/l) 293B (10 mu mol/l) reduced the conductance (G(m)). In oocytes coinjected with the sense probe for XK(v)LQT and pretreated with IBMX 293B still reduced G(m), whilst the 293B-inhibitable G(m) was almost completely absent in oocytes coinjected with XK(v)LQT antisense. In another series a full length clone for mK(v)LQT was generated by PCR techniques and the cRNA was injected into oocytes. After several days these oocytes, unlike water injected ones, were found to be strongly hyperpolarized and their G(m) was increased significantly. The oocytes were depolarized significantly and their G(m) was reduced reversibly by 10 mu mol/l 293B. These data indicate that CFTR activation by IBMX indeed co-activates an endogenous oocyte XK(v)LQT channel and that this channel is inhibited by a new class of channel blockers, of which 293B is the prototype.