State-dependent barium block of wild-type and inactivation-deficient HERG channels in Xenopus oocytes. Export

@article{Weerapura2000_herg_model, abstract = {The effects of Ba2+ on current resulting from the heterologous expression of the human ether-\`{a}-go-go related gene (HERG) (IHERG) was studied with two-electrode voltage clamp techniques in Xenopus oocytes. Ba2+ produced time- and voltage-dependent block of IHERG. Significant inhibition was seen at concentrations as low as 1 microM. Inhibition was greatest at step potentials between -40 and 0 mV; at more positive potentials, inhibition decreased in association with time-dependent unblocking of channels. An inactivation-attenuated mutant of HERG (S631A) was prepared and expressed in Xenopus oocytes. Ba2+ block of S631A differed from that of HERG in that extensive unblocking was no longer seen at positive potentials and the voltage dependence of step current block was greatly attenuated. A mathematical model was applied to analyse quantitatively the inhibitory effects of Ba2+ on IHERG. The model suggested similar voltage-dependent affinity of Ba2+ for the open and closed states, along with absence of binding to the inactivated state, and accounted well for Ba2+ effects on both wild-type and S631A channels. We conclude that Ba2+ potently inhibits IHERG in a characteristic state-dependent fashion, with strong unblocking at positive potentials related to the presence of an intact C-type inactivation mechanism.}, address = {Research Center, Departments of Medicine and Anesthesia, Montreal Heart Institute, 5000 Belanger Street East, Montreal, Canada.}, author = {Weerapura, M. and Nattel, S. and Courtemanche, M. and Doern, D. and Ethier, N. and Hebert, T.}, citeulike-article-id = {1093782}, citeulike-linkout-0 = {http://view.ncbi.nlm.nih.gov/pubmed/10896755}, citeulike-linkout-1 = {http://www.hubmed.org/display.cgi?uids=10896755}, day = {15}, issn = {0022-3751}, journal = {J Physiol}, keywords = {drug, herg, inhibition}, month = {July}, pages = {265--278}, posted-at = {2007-02-07 21:49:11}, priority = {4}, title = {State-dependent barium block of wild-type and inactivation-deficient HERG channels in Xenopus oocytes.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/10896755}, volume = {526 Pt 2}, year = {2000} }

TY - JOUR ID - Weerapura2000_herg_model L3 - citeulike-article-id:1093782 N2 - The effects of Ba2+ on current resulting from the heterologous expression of the human ether-à-go-go related gene (HERG) (IHERG) was studied with two-electrode voltage clamp techniques in Xenopus oocytes. Ba2+ produced time- and voltage-dependent block of IHERG. Significant inhibition was seen at concentrations as low as 1 microM. Inhibition was greatest at step potentials between -40 and 0 mV; at more positive potentials, inhibition decreased in association with time-dependent unblocking of channels. An inactivation-attenuated mutant of HERG (S631A) was prepared and expressed in Xenopus oocytes. Ba2+ block of S631A differed from that of HERG in that extensive unblocking was no longer seen at positive potentials and the voltage dependence of step current block was greatly attenuated. A mathematical model was applied to analyse quantitatively the inhibitory effects of Ba2+ on IHERG. The model suggested similar voltage-dependent affinity of Ba2+ for the open and closed states, along with absence of binding to the inactivated state, and accounted well for Ba2+ effects on both wild-type and S631A channels. We conclude that Ba2+ potently inhibits IHERG in a characteristic state-dependent fashion, with strong unblocking at positive potentials related to the presence of an intact C-type inactivation mechanism. JF - J Physiol SN - 0022-3751 AD - Research Center, Departments of Medicine and Anesthesia, Montreal Heart Institute, 5000 Belanger Street East, Montreal, Canada. EP - 278 TI - State-dependent barium block of wild-type and inactivation-deficient HERG channels in Xenopus oocytes. VL - 526 Pt 2 SP - 265 KW - drug KW - herg KW - inhibition AU - Weerapura, M AU - Nattel, S AU - Courtemanche, M AU - Doern, D AU - Ethier, N AU - Hebert, T PY - 2000/07/15/ UR - http://view.ncbi.nlm.nih.gov/pubmed/10896755 ER -