K V LQT channels are inhibited by the K + channel blocker 293B

Abstract

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 KVLQT 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 KVLQT (XKVLQT), and is mouse KVLQT (mKVLQT) expressed in oocytes inhibited by 293B? Antisense and sense probes for XKVLQT 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 micromol/l) reduced the conductance (Gm). In oocytes coinjected with the sense probe for XKVLQT and pretreated with IBMX 293B still reduced Gm, whilst the 293B-inhibitable Gm was almost completely absent in oocytes coinjected with XKVLQT antisense. In another series a full length clone for mKVLQT 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 Gm was increased significantly. The oocytes were depolarized significantly and their Gm was reduced reversibly by 10 micromol/l 293B. These data indicate that CFTR activation by IBMX indeed co-activates an endogenous oocyte XKVLQT channel and that this channel is inhibited by a new class of channel blockers, of which 293B is the prototype.

Modulation of potassium channel function confers a hyperproliferative invasive phenotype on embryonic stem cells

“…Exposure at stage 41 to Chromanol 293B, a specific blocker of KCNQ1 (27), also resulted in hyperpigmentation (Fig. S3), consistent with inhibition of KCNQ1 being responsible for hyperpigmentation.…”

Expression of Cystic Fibrosis Transmembrane Conductance Regulator Alters the Responses to Hypotonic Cell Swelling and ATP of Chinese Hamster Ovary Cells

“…In our previous experiments utilizing forskolin and IBMX [16] all the resident Cl -channels might have been activated maximally. This hypothesis would agree with a previous study [35] in which we showed that the effects of neurotensin and ATP in HT 29 could be potentiated by cAMP. The present studies would also be in agreement with other hypotheses of CFTR regulation of other as yet unidentified pathways.…”

“…This latter conclusion may not be correct because CHO cells possess small endogenous Cl -channels [28] and because CFTR can also generate a variety of indirect effects. These can be summarized as follows: interference with membrane trafficking [13][14][15], inhibition of epithelial Na + channels (ENaC) [4,6,7]; modulation of Kir1.1 (ROMK1) K + channels [9]; interaction with I Ks (K v LQT 1 and minK) [8,29], and modulation of water transport [11].…”

Enhancement of P2Y₆-Induced Cl^- Secretion by IL-13 and Modulation of SK4 Channels Activity in Human Bronchial Cells

“…We therefore investigated the possible implication of K cAMP channels in the UDP-mediated I sc stimulation. In IL-13-treated NHBE cells, chromanol 293B (100 µM), a specific inhibitor of the KCNQ1 channel, part of the K cAMP channel [12,[48][49][50] did not affect the amplitude of the two UDPstimulated I sc components (I fast was of 24.8 ± 2.9 µA.cm in absence or presence of chromanol respectively, n=6). Chromanol effect on basolateral 86 Rb effluxes was also investigated upon UDP application.…”