One drug-sensitive subunit is sufficient for a near-maximal retigabine effect in KCNQ channels
| Autor: | Michael C. Yau, Harley T. Kurata, Stephan A. Pless, Jingru Li, Caroline K. Wang, Tarek Ammar, Robin Y. Kim, Runying Y. Yang |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Physiology Chemistry Retigabine Protein subunit Antiepileptic drug Phenylenediamines 3. Good health KCNQ3 Potassium Channel 03 medical and health sciences chemistry.chemical_compound Xenopus laevis 030104 developmental biology Kcnq channels Mutation Biophysics Animals Voltage dependence Anticonvulsants Carbamates Research Articles Research Article |
| Zdroj: | The Journal of General Physiology |
| ISSN: | 1540-7748 0022-1295 |
| Popis: | Retigabine is a widely studied potassium channel activator that is thought to interact with a conserved Trp side chain in the pore domain of Kv7 subunits. Yau et al. demonstrate that drug sensitivity in just one of the four subunits is sufficient for a near-maximal response to retigabine. 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 drug-sensitive subunits for maximal effect. |
| Databáze: | OpenAIRE |
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