One drug-sensitive subunit is sufficient for a nearmaximal retigabine effect in KCNQ channels

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Standard

One drug-sensitive subunit is sufficient for a nearmaximal retigabine effect in KCNQ channels. / Yau, Michael C.; Kim, Robin Y.; Wang, Caroline K.; Li, Jingru; Ammar, Tarek; Yang, Runying Y.; Pless, Stephan A.; Kurata, Harley T.

In: Journal of General Physiology, Vol. 215, No. 10, 01.10.2018, p. 1421-1431.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Yau, MC, Kim, RY, Wang, CK, Li, J, Ammar, T, Yang, RY, Pless, SA & Kurata, HT 2018, 'One drug-sensitive subunit is sufficient for a nearmaximal retigabine effect in KCNQ channels', Journal of General Physiology, vol. 215, no. 10, pp. 1421-1431. https://doi.org/10.1085/jgp.201812013

APA

Yau, M. C., Kim, R. Y., Wang, C. K., Li, J., Ammar, T., Yang, R. Y., Pless, S. A., & Kurata, H. T. (2018). One drug-sensitive subunit is sufficient for a nearmaximal retigabine effect in KCNQ channels. Journal of General Physiology, 215(10), 1421-1431. https://doi.org/10.1085/jgp.201812013

Vancouver

Yau MC, Kim RY, Wang CK, Li J, Ammar T, Yang RY et al. One drug-sensitive subunit is sufficient for a nearmaximal retigabine effect in KCNQ channels. Journal of General Physiology. 2018 Oct 1;215(10):1421-1431. https://doi.org/10.1085/jgp.201812013

Author

Yau, Michael C. ; Kim, Robin Y. ; Wang, Caroline K. ; Li, Jingru ; Ammar, Tarek ; Yang, Runying Y. ; Pless, Stephan A. ; Kurata, Harley T. / One drug-sensitive subunit is sufficient for a nearmaximal retigabine effect in KCNQ channels. In: Journal of General Physiology. 2018 ; Vol. 215, No. 10. pp. 1421-1431.

Bibtex

@article{900df6a55f784255940c1ea45dfe6b3a,
title = "One drug-sensitive subunit is sufficient for a nearmaximal retigabine effect in KCNQ channels",
abstract = "Retigabine is an antiepileptic drug and the first voltage-gated potassium (Kv) channel opener to be approved for human therapeutic use. Retigabine is thought to interact with a conserved Trp side chain in the pore of KCNQ2-5 (Kv7.2-7.5) channels, causing a pronounced hyperpolarizing shift in the voltage dependence of activation. In this study, we investigate the functional stoichiometry of retigabine actions by manipulating the number of retigabine-sensitive subunits in concatenated KCNQ3 channel tetramers. We demonstrate that intermediate retigabine concentrations cause channels to exhibit biphasic conductance-voltage relationships rather than progressive concentration-dependent shifts. This suggests that retigabine can exert its effects in a nearly {"}all-or-none{"} manner, such that channels exhibit either fully shifted or unshifted behavior. Supporting this notion, concatenated channels containing only a single retigabine-sensitive subunit exhibit a nearly maximal retigabine effect. Also, rapid solution exchange experiments reveal delayed kinetics during channel closure, as retigabine dissociates from channels with multiple drug-sensitive subunits. Collectively, these data suggest that a single retigabine-sensitive subunit can generate a large shift of the KCNQ3 conductance-voltage relationship. In a companion study (Wang et al. 2018. J. Gen. Physiol. https:// doi .org/ 10 .1085/ jgp .201812014), we contrast these findings with the stoichiometry of a voltage sensor-targeted KCNQ channel opener (ICA-069673), which requires four drugsensitive subunits for maximal effect.",
author = "Yau, {Michael C.} and Kim, {Robin Y.} and Wang, {Caroline K.} and Jingru Li and Tarek Ammar and Yang, {Runying Y.} and Pless, {Stephan A.} and Kurata, {Harley T.}",
year = "2018",
month = oct,
day = "1",
doi = "10.1085/jgp.201812013",
language = "English",
volume = "215",
pages = "1421--1431",
journal = "Journal of General Physiology",
issn = "0022-1295",
publisher = "Rockefeller University Press",
number = "10",

}

RIS

TY - JOUR

T1 - One drug-sensitive subunit is sufficient for a nearmaximal retigabine effect in KCNQ channels

AU - Yau, Michael C.

AU - Kim, Robin Y.

AU - Wang, Caroline K.

AU - Li, Jingru

AU - Ammar, Tarek

AU - Yang, Runying Y.

AU - Pless, Stephan A.

AU - Kurata, Harley T.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Retigabine is an antiepileptic drug and the first voltage-gated potassium (Kv) channel opener to be approved for human therapeutic use. Retigabine is thought to interact with a conserved Trp side chain in the pore of KCNQ2-5 (Kv7.2-7.5) channels, causing a pronounced hyperpolarizing shift in the voltage dependence of activation. In this study, we investigate the functional stoichiometry of retigabine actions by manipulating the number of retigabine-sensitive subunits in concatenated KCNQ3 channel tetramers. We demonstrate that intermediate retigabine concentrations cause channels to exhibit biphasic conductance-voltage relationships rather than progressive concentration-dependent shifts. This suggests that retigabine can exert its effects in a nearly "all-or-none" manner, such that channels exhibit either fully shifted or unshifted behavior. Supporting this notion, concatenated channels containing only a single retigabine-sensitive subunit exhibit a nearly maximal retigabine effect. Also, rapid solution exchange experiments reveal delayed kinetics during channel closure, as retigabine dissociates from channels with multiple drug-sensitive subunits. Collectively, these data suggest that a single retigabine-sensitive subunit can generate a large shift of the KCNQ3 conductance-voltage relationship. In a companion study (Wang et al. 2018. J. Gen. Physiol. https:// doi .org/ 10 .1085/ jgp .201812014), we contrast these findings with the stoichiometry of a voltage sensor-targeted KCNQ channel opener (ICA-069673), which requires four drugsensitive subunits for maximal effect.

AB - Retigabine is an antiepileptic drug and the first voltage-gated potassium (Kv) channel opener to be approved for human therapeutic use. Retigabine is thought to interact with a conserved Trp side chain in the pore of KCNQ2-5 (Kv7.2-7.5) channels, causing a pronounced hyperpolarizing shift in the voltage dependence of activation. In this study, we investigate the functional stoichiometry of retigabine actions by manipulating the number of retigabine-sensitive subunits in concatenated KCNQ3 channel tetramers. We demonstrate that intermediate retigabine concentrations cause channels to exhibit biphasic conductance-voltage relationships rather than progressive concentration-dependent shifts. This suggests that retigabine can exert its effects in a nearly "all-or-none" manner, such that channels exhibit either fully shifted or unshifted behavior. Supporting this notion, concatenated channels containing only a single retigabine-sensitive subunit exhibit a nearly maximal retigabine effect. Also, rapid solution exchange experiments reveal delayed kinetics during channel closure, as retigabine dissociates from channels with multiple drug-sensitive subunits. Collectively, these data suggest that a single retigabine-sensitive subunit can generate a large shift of the KCNQ3 conductance-voltage relationship. In a companion study (Wang et al. 2018. J. Gen. Physiol. https:// doi .org/ 10 .1085/ jgp .201812014), we contrast these findings with the stoichiometry of a voltage sensor-targeted KCNQ channel opener (ICA-069673), which requires four drugsensitive subunits for maximal effect.

U2 - 10.1085/jgp.201812013

DO - 10.1085/jgp.201812013

M3 - Journal article

C2 - 30166314

AN - SCOPUS:85054065563

VL - 215

SP - 1421

EP - 1431

JO - Journal of General Physiology

JF - Journal of General Physiology

SN - 0022-1295

IS - 10

ER -

ID: 204112889