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Specific block of cloned Herg channels by clofilium and its tertiary analog LY97241.
FEBS Lett. 1997 Sep 08; 414(2):435-8.FL

Abstract

The class III antiarrhythmic drug clofilium is known to block diverse delayed rectifier K+ channels at micromolar concentrations. In the present study we investigated the potency of clofilium and its tertiary analog LY97241 to inhibit K+ channels, encoded by the human ether-a-go-go related gene (HERG). Clofilium blocked HERG channels in a voltage-dependent fashion with an IC50 of 250 nM and 150 nM at 0 and +40 mV, respectively. LY97241 was almost 10-fold more potent (IC50 of 19 nM at +40 mV). Other cloned K+ channels which are also expressed in cardiac tissue, Kv1.1, Kv1.2, Kv1.4, Kv1.5, Kv4.2, Kir2.1, or I(Ks), were not affected by 100-fold higher concentrations. Block of HERG channels by LY97241 was voltage dependent and the rate of HERG inactivation was increased by LY97241. A rise of [K+]0 decreased both, rate of HERG inactivation and LY97241 affinity. The HERG S631A and S620T mutant channels which have a strongly reduced degree of inactivation were 7-fold and 33-fold less sensitive to LY97241 blockade, indicating that LY97241 binding is affected by HERG channel inactivation. In summary, the antiarrhythmic action of clofilium and its analog LY97241 appears to be caused by their potent, but distinct ability for blocking HERG channels.

Authors+Show Affiliations

Institute of Physiology I, Eberhard Karls University Tübingen, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9315735

Citation

Suessbrich, H, et al. "Specific Block of Cloned Herg Channels By Clofilium and Its Tertiary Analog LY97241." FEBS Letters, vol. 414, no. 2, 1997, pp. 435-8.
Suessbrich H, Schönherr R, Heinemann SH, et al. Specific block of cloned Herg channels by clofilium and its tertiary analog LY97241. FEBS Lett. 1997;414(2):435-8.
Suessbrich, H., Schönherr, R., Heinemann, S. H., Lang, F., & Busch, A. E. (1997). Specific block of cloned Herg channels by clofilium and its tertiary analog LY97241. FEBS Letters, 414(2), 435-8.
Suessbrich H, et al. Specific Block of Cloned Herg Channels By Clofilium and Its Tertiary Analog LY97241. FEBS Lett. 1997 Sep 8;414(2):435-8. PubMed PMID: 9315735.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Specific block of cloned Herg channels by clofilium and its tertiary analog LY97241. AU - Suessbrich,H, AU - Schönherr,R, AU - Heinemann,S H, AU - Lang,F, AU - Busch,A E, PY - 1997/10/7/pubmed PY - 1997/10/7/medline PY - 1997/10/7/entrez SP - 435 EP - 8 JF - FEBS letters JO - FEBS Lett VL - 414 IS - 2 N2 - The class III antiarrhythmic drug clofilium is known to block diverse delayed rectifier K+ channels at micromolar concentrations. In the present study we investigated the potency of clofilium and its tertiary analog LY97241 to inhibit K+ channels, encoded by the human ether-a-go-go related gene (HERG). Clofilium blocked HERG channels in a voltage-dependent fashion with an IC50 of 250 nM and 150 nM at 0 and +40 mV, respectively. LY97241 was almost 10-fold more potent (IC50 of 19 nM at +40 mV). Other cloned K+ channels which are also expressed in cardiac tissue, Kv1.1, Kv1.2, Kv1.4, Kv1.5, Kv4.2, Kir2.1, or I(Ks), were not affected by 100-fold higher concentrations. Block of HERG channels by LY97241 was voltage dependent and the rate of HERG inactivation was increased by LY97241. A rise of [K+]0 decreased both, rate of HERG inactivation and LY97241 affinity. The HERG S631A and S620T mutant channels which have a strongly reduced degree of inactivation were 7-fold and 33-fold less sensitive to LY97241 blockade, indicating that LY97241 binding is affected by HERG channel inactivation. In summary, the antiarrhythmic action of clofilium and its analog LY97241 appears to be caused by their potent, but distinct ability for blocking HERG channels. SN - 0014-5793 UR - https://www.unboundmedicine.com/medline/citation/9315735/Specific_block_of_cloned_Herg_channels_by_clofilium_and_its_tertiary_analog_LY97241_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-5793(97)01030-2 DB - PRIME DP - Unbound Medicine ER -