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Probing the interaction between inactivation gating and Dd-sotalol block of HERG.
Circ Res. 2000 Nov 24; 87(11):1012-8.CircR

Abstract

Potassium channels encoded by HERG underlie I:(Kr), a sensitive target for most class III antiarrhythmic drugs, including methanesulfonanilides such as Dd-sotalol. Recently it was shown that these drugs are trapped in the channel as it closes during hyperpolarization. At the same time, HERG channels rapidly open and inactivate when depolarized, and methanesulfonanilide block is known to develop in a use-dependent manner, suggesting a potential role for inactivation in drug binding. However, the role of HERG inactivation in class III drug action is uncertain: pore mutations that remove inactivation reduce block, yet many of these mutations also modify the channel permeation properties and could alter drug affinity through gating-independent mechanisms. In the present study, we identify a definitive role for inactivation gating in Dd-sotalol block of HERG, using interventions complementary to mutagenesis. These interventions (addition of extracellular Cd(2+), removal of extracellular Na(+)) modify the voltage dependence of inactivation but not activation. In normal extracellular solutions, block of HERG current by 300 micromol/L Dd-sotalol reached 80% after a 10-minute period of repetitive depolarization to +20 mV. Maneuvers that impeded steady-state inactivation also reduced Dd-sotalol block of HERG: 100 micromol/L Cd(2+) reduced steady-state block to 55% at +20 mV (P:<0.05); removing extracellular Na(+) reduced block to 44% (P:<0.05). An inactivation-disabling mutation (G628C-S631C) reduced Dd-sotalol block to only 11% (P:<0.05 versus wild type). However, increasing the rate of channel inactivation by depolarizing to +60 mV reduced Dd-sotalol block to 49% (P:<0.05 versus +20 mV), suggesting that the drug does not primarily bind to the inactivated state. Coexpression of MiRP1 with HERG had no effect on inactivation gating and did not modify Dd-sotalol block. We postulate that Dd-sotalol accesses its receptor in the open pore, and the drug-receptor interaction is then stabilized by inactivation. Whereas deactivation traps the bound methanesulfonanilide during hyperpolarization, we propose that HERG inactivation stabilizes the drug-receptor interaction during membrane depolarization.

Authors+Show Affiliations

Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

11090546

Citation

Numaguchi, H, et al. "Probing the Interaction Between Inactivation Gating and Dd-sotalol Block of HERG." Circulation Research, vol. 87, no. 11, 2000, pp. 1012-8.
Numaguchi H, Mullins FM, Johnson JP, et al. Probing the interaction between inactivation gating and Dd-sotalol block of HERG. Circ Res. 2000;87(11):1012-8.
Numaguchi, H., Mullins, F. M., Johnson, J. P., Johns, D. C., Po, S. S., Yang, I. C., Tomaselli, G. F., & Balser, J. R. (2000). Probing the interaction between inactivation gating and Dd-sotalol block of HERG. Circulation Research, 87(11), 1012-8.
Numaguchi H, et al. Probing the Interaction Between Inactivation Gating and Dd-sotalol Block of HERG. Circ Res. 2000 Nov 24;87(11):1012-8. PubMed PMID: 11090546.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Probing the interaction between inactivation gating and Dd-sotalol block of HERG. AU - Numaguchi,H, AU - Mullins,F M, AU - Johnson,J P,Jr AU - Johns,D C, AU - Po,S S, AU - Yang,I C, AU - Tomaselli,G F, AU - Balser,J R, PY - 2000/11/25/pubmed PY - 2001/2/28/medline PY - 2000/11/25/entrez SP - 1012 EP - 8 JF - Circulation research JO - Circ Res VL - 87 IS - 11 N2 - Potassium channels encoded by HERG underlie I:(Kr), a sensitive target for most class III antiarrhythmic drugs, including methanesulfonanilides such as Dd-sotalol. Recently it was shown that these drugs are trapped in the channel as it closes during hyperpolarization. At the same time, HERG channels rapidly open and inactivate when depolarized, and methanesulfonanilide block is known to develop in a use-dependent manner, suggesting a potential role for inactivation in drug binding. However, the role of HERG inactivation in class III drug action is uncertain: pore mutations that remove inactivation reduce block, yet many of these mutations also modify the channel permeation properties and could alter drug affinity through gating-independent mechanisms. In the present study, we identify a definitive role for inactivation gating in Dd-sotalol block of HERG, using interventions complementary to mutagenesis. These interventions (addition of extracellular Cd(2+), removal of extracellular Na(+)) modify the voltage dependence of inactivation but not activation. In normal extracellular solutions, block of HERG current by 300 micromol/L Dd-sotalol reached 80% after a 10-minute period of repetitive depolarization to +20 mV. Maneuvers that impeded steady-state inactivation also reduced Dd-sotalol block of HERG: 100 micromol/L Cd(2+) reduced steady-state block to 55% at +20 mV (P:<0.05); removing extracellular Na(+) reduced block to 44% (P:<0.05). An inactivation-disabling mutation (G628C-S631C) reduced Dd-sotalol block to only 11% (P:<0.05 versus wild type). However, increasing the rate of channel inactivation by depolarizing to +60 mV reduced Dd-sotalol block to 49% (P:<0.05 versus +20 mV), suggesting that the drug does not primarily bind to the inactivated state. Coexpression of MiRP1 with HERG had no effect on inactivation gating and did not modify Dd-sotalol block. We postulate that Dd-sotalol accesses its receptor in the open pore, and the drug-receptor interaction is then stabilized by inactivation. Whereas deactivation traps the bound methanesulfonanilide during hyperpolarization, we propose that HERG inactivation stabilizes the drug-receptor interaction during membrane depolarization. SN - 1524-4571 UR - https://www.unboundmedicine.com/medline/citation/11090546/Probing_the_interaction_between_inactivation_gating_and_Dd_sotalol_block_of_HERG_ L2 - https://www.ahajournals.org/doi/10.1161/01.res.87.11.1012?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -