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Inactivation gating determines drug potency: a common mechanism for drug blockade of HERG channels.
Acta Pharmacol Sin. 2004 May; 25(5):554-60.AP

Abstract

AIM

To determine the mechanisms of interactions between different drugs and HERG channels.

METHODS

Various antiarrhythmic (dofetilide, quinidine, azimilide, RP58866) and non-antiarrhythmic (terfenadine, nicotine) agents were used on HERG channels expressed in Xenopus oocyte. Whole-cell voltage-clamp techniques were used.

RESULTS

All drugs produced concentration-dependent block of HERG current. The inhibition was markedly facilitated with voltage protocols favoring channel inactivation (eg, less negative holding potentials). Maneuvers that weakened channel inactivation (eg, elevation of external K+), relieved HERG blockade by all drugs. Moreover, the inhibitory potency was reduced by at least 20-300 fold with varying compounds when rapid C-type inactivation was removed by a mutation located between the transmembrane domains 5 and 6 (S631A).

CONCLUSION

The inactivation gating of HERG channels determines the blocking potency of drugs. This mechanism might be common to drugs of various classes.

Authors+Show Affiliations

Department of Pharmacology, Harbin Medical University, Harbin 150086, China. xuchaoqian@0451.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15132818

Citation

Yang, Bao-feng, et al. "Inactivation Gating Determines Drug Potency: a Common Mechanism for Drug Blockade of HERG Channels." Acta Pharmacologica Sinica, vol. 25, no. 5, 2004, pp. 554-60.
Yang BF, Xu DH, Xu CQ, et al. Inactivation gating determines drug potency: a common mechanism for drug blockade of HERG channels. Acta Pharmacol Sin. 2004;25(5):554-60.
Yang, B. F., Xu, D. H., Xu, C. Q., Li, Z., Du, Z. M., Wang, H. Z., & Dong, D. L. (2004). Inactivation gating determines drug potency: a common mechanism for drug blockade of HERG channels. Acta Pharmacologica Sinica, 25(5), 554-60.
Yang BF, et al. Inactivation Gating Determines Drug Potency: a Common Mechanism for Drug Blockade of HERG Channels. Acta Pharmacol Sin. 2004;25(5):554-60. PubMed PMID: 15132818.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inactivation gating determines drug potency: a common mechanism for drug blockade of HERG channels. AU - Yang,Bao-feng, AU - Xu,Dong-hui, AU - Xu,Chao-qian, AU - Li,Zhe, AU - Du,Zhi-min, AU - Wang,Hui-zhen, AU - Dong,De-li, PY - 2004/5/11/pubmed PY - 2004/8/11/medline PY - 2004/5/11/entrez SP - 554 EP - 60 JF - Acta pharmacologica Sinica JO - Acta Pharmacol Sin VL - 25 IS - 5 N2 - AIM: To determine the mechanisms of interactions between different drugs and HERG channels. METHODS: Various antiarrhythmic (dofetilide, quinidine, azimilide, RP58866) and non-antiarrhythmic (terfenadine, nicotine) agents were used on HERG channels expressed in Xenopus oocyte. Whole-cell voltage-clamp techniques were used. RESULTS: All drugs produced concentration-dependent block of HERG current. The inhibition was markedly facilitated with voltage protocols favoring channel inactivation (eg, less negative holding potentials). Maneuvers that weakened channel inactivation (eg, elevation of external K+), relieved HERG blockade by all drugs. Moreover, the inhibitory potency was reduced by at least 20-300 fold with varying compounds when rapid C-type inactivation was removed by a mutation located between the transmembrane domains 5 and 6 (S631A). CONCLUSION: The inactivation gating of HERG channels determines the blocking potency of drugs. This mechanism might be common to drugs of various classes. SN - 1671-4083 UR - https://www.unboundmedicine.com/medline/citation/15132818/Inactivation_gating_determines_drug_potency:_a_common_mechanism_for_drug_blockade_of_HERG_channels_ L2 - http://www.chinaphar.com/1671-4083/25/554.pdf DB - PRIME DP - Unbound Medicine ER -