Journal article
Sites and Functional Consequence of Alkylphenol Anesthetic Binding to Kv1.2 Channels
Molecular neurobiology, v 55(2), pp 1692-1702
01 Feb 2018
PMID: 28204960
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Inhalational general anesthetics, such as sevoflurane and isoflurane, modulate a subset of brain Kv1 potassium channels. However, the Kv1.2 channel is resistant to propofol, a commonly used intravenous alkylphenol anesthetic. We hypothesize that propofol binds to a presumed pocket involving the channel's S4-S5 linker, but functional transduction is poor and, therefore, propofol efficacy is low. To test this hypothesis, we used a photoactive propofol analog (meta-aziPropofol = AziPm) to directly probe binding and electrophysiological and mutational analyses in Xenopus oocytes to probe function. We find that AziPm photolabels L321 in the S4-S5 linker of both the wild-type Kv1.2 and a mutant Kv1.2 (G329 T) with a novel gating phenotype. Furthermore, whereas propofol does not significantly modulate Kv1.2 WT but robustly potentiates Kv1.2 G329T, AziPm inhibits Kv1.2 WT and also potentiates Kv1.2 G329T. Kv1.2 modulation by AziPm was abolished by two mutations that decreased hydrophobicity at L321 (L321A and L321F), confirming the specific significance of the S4-S5 linker in the mechanism of general anesthetic modulation. Since AziPm binds to Kv1.2 G329T and shares the propofol ability to potentiate this mutant, the parent propofol likely also binds to the Kv1.2 channel. However, binding and alkylphenol-induced transduction are seemingly sensitive to the conformation of the S4-S5 linker site (altered by G329T) and subtle differences in the chemical structures of propofol and AziPm. Overall, the results are consistent with a mechanism of general anesthetic modulation that depends on the complementarity of necessary ligand binding and permissive ion channel conformations that dictate modulation and efficacy.
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Details
- Title
- Sites and Functional Consequence of Alkylphenol Anesthetic Binding to Kv1.2 Channels
- Creators
- Weiming Bu - University of PennsylvaniaQiansheng Liang - Thomas Jefferson UniversityLianteng Zhi - Thomas Jefferson UniversityLina Maciunas - Drexel UniversityPatrick J. Loll - Drexel UniversityRoderic G. Eckenhoff - University of PennsylvaniaManuel Covarrubias - Thomas Jefferson University
- Publication Details
- Molecular neurobiology, v 55(2), pp 1692-1702
- Publisher
- Humana Press Inc
- Number of pages
- 11
- Grant note
- P01 GM055876 / National Institutes of Health, US Department of Health and Human Services; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000425624000065
- Scopus ID
- 2-s2.0-85012920675
- Other Identifier
- 991019170382404721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Neurosciences