Journal article
The membrane electric field regulates the PIP2-binding site to gate the KCNQ1 channel
Proceedings of the National Academy of Sciences - PNAS, Vol.120(21), p.1
05/23/2023
DOI: 10.1073/pnas.2301985120
PMCID: PMC10214144
PMID: 37192161
Abstract
SignificanceVoltage-gated ion channels underlie electrical signaling in cells. The structures and functions of voltage-dependent K+, Na+, and Ca2+ and transient receptor potential ion channels have been studied extensively since their discovery. Despite these efforts, it is still not well understood how the voltage sensors in these different ion channels change their conformation in response to membrane voltage changes, and how these movements regulate the opening or closing of the channel’s gate. This study presents structures of the human KCNQ1 (Kv7.1) voltage–dependent and phosphatidylinositol 4,5-bisphosphate (PIP2)-dependent K+ channel in electrically polarized lipid vesicles using cryogenic electron microscopy, showing how the voltage sensors influence gating indirectly by regulating the ability of PIP2 to bind to the channel.
Voltage-dependent ion channels underlie the propagation of action potentials and other forms of electrical activity in cells. In these proteins, voltage sensor domains (VSDs) regulate opening and closing of the pore through the displacement of their positive-charged S4 helix in response to the membrane voltage. The movement of S4 at hyperpolarizing membrane voltages in some channels is thought to directly clamp the pore shut through the S4–S5 linker helix. The KCNQ1 channel (also known as Kv7.1), which is important for heart rhythm, is regulated not only by membrane voltage but also by the signaling lipid phosphatidylinositol 4,5-bisphosphate (PIP2). KCNQ1 requires PIP2 to open and to couple the movement of S4 in the VSD to the pore. To understand the mechanism of this voltage regulation, we use cryogenic electron microscopy to visualize the movement of S4 in the human KCNQ1 channel in lipid membrane vesicles with a voltage difference across the membrane, i.e., an applied electric field in the membrane. Hyperpolarizing voltages displace S4 in such a manner as to sterically occlude the PIP2-binding site. Thus, in KCNQ1, the voltage sensor acts primarily as a regulator of PIP2 binding. The voltage sensors’ influence on the channel’s gate is indirect through the reaction sequence: voltage sensor movement → alter PIP2 ligand affinity → alter pore opening.
Details
- Title: Subtitle
- The membrane electric field regulates the PIP2-binding site to gate the KCNQ1 channel
- Creators
- Venkata Shiva Mandala - Rockefeller UniversityRoderick MacKinnon - Rockefeller University
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.120(21), p.1
- DOI
- 10.1073/pnas.2301985120
- PMID
- 37192161
- PMCID
- PMC10214144
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Number of pages
- 12
- Grant note
- HHMI / Howard Hughes Medical Institute (HHMI) (100000011) JCC / Jane Coffin Childs Memorial Fund for Medical Research (JCC) (100001033)
- Language
- English
- Date published
- 05/23/2023
- Academic Unit
- Biochemistry and Molecular Biology
- Record Identifier
- 9985112883002771
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