Journal article
Voltage-sensor movements in the Eag Kv channel under an applied electric field
Proceedings of the National Academy of Sciences - PNAS, Vol.119(46), pp.1-12
11/15/2022
DOI: 10.1073/pnas.2214151119
PMCID: PMC9674223
PMID: 36331999
Abstract
Voltage-dependent ion channels underlie the action potential and other forms of electrical activity in cells. They have been the subjects of much study since Hodgkin and Huxley described the electrical origins of the action potential in 1952. Over the past two decades, structures of voltage-dependent K+, Na+, Ca2+, hyperpolarization-activated cyclic nucleotide–gated and transient receptor potential channels have been determined. The biggest question that remains regarding the structure and mechanism of this entire class of ion channels is: How do the voltage sensors respond to an applied electric field across the membrane? This study presents structures of the Eag voltage-dependent K+ channel in electrically polarized lipid vesicles, using cryo-electron microscopy and showing how the voltage sensors regulate the pore. Voltage-dependent ion channels regulate the opening of their pores by sensing the membrane voltage. This process underlies the propagation of action potentials and other forms of electrical activity in cells. The voltage dependence of these channels is governed by the transmembrane displacement of the positive charged S4 helix within their voltage-sensor domains. We use cryo-electron microscopy to visualize this movement in the mammalian Eag voltage-dependent potassium channel in lipid membrane vesicles with a voltage difference across the membrane. Multiple structural configurations show that the applied electric field displaces S4 toward the cytoplasm by two helical turns, resulting in an extended interfacial helix near the inner membrane leaflet. The position of S4 in this down conformation is sterically incompatible with an open pore, thus explaining how movement of the voltage sensor at hyperpolarizing membrane voltages locks the pore shut in this kind of voltage-dependent K+ (Kv) channel. The structures solved in lipid bilayer vesicles detail the intricate interplay between Kv channels and membranes, from showing how arginines are stabilized deep within the membrane and near phospholipid headgroups, to demonstrating how the channel reshapes the inner leaflet of the membrane itself.
Details
- Title: Subtitle
- Voltage-sensor movements in the Eag Kv channel under an applied electric field
- Creators
- Venkata Shiva Mandala - Rockefeller UniversityRoderick MacKinnon - Rockefeller University
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.119(46), pp.1-12
- DOI
- 10.1073/pnas.2214151119
- PMID
- 36331999
- PMCID
- PMC9674223
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Grant note
- HHMI / Howard Hughes Medical Institute (HHMI)
- Language
- English
- Date published
- 11/15/2022
- Academic Unit
- Biochemistry and Molecular Biology
- Record Identifier
- 9985113010702771
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