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J Biol Chem. 2018 Dec 14;293(50):19411-19428. doi: 10.1074/jbc.RA118.005401. Epub 2018 Oct 22.

Phosphatidylinositol 4,5-bisphosphate (PIP2) regulates KCNQ3 K+ channels by interacting with four cytoplasmic channel domains.

Author information

1
From the Department of Cell and Integrative Physiology, University of Texas Health San Antonio, San Antonio, Texas 78229.
2
the Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, and ciria@umich.edu.
3
the Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109.
4
From the Department of Cell and Integrative Physiology, University of Texas Health San Antonio, San Antonio, Texas 78229, shapirom@uthscsa.edu.

Abstract

Phosphatidylinositol 4,5-bisphosphate (PIP2) in the plasma membrane regulates the function of many ion channels, including M-type (potassium voltage-gated channel subfamily Q member (KCNQ), Kv7) K+ channels; however, the molecular mechanisms involved remain unclear. To this end, we here focused on the KCNQ3 subtype that has the highest apparent affinity for PIP2 and performed extensive mutagenesis in regions suggested to be involved in PIP2 interactions among the KCNQ family. Using perforated patch-clamp recordings of heterologously transfected tissue culture cells, total internal reflection fluorescence microscopy, and the zebrafish (Danio rerio) voltage-sensitive phosphatase to deplete PIP2 as a probe, we found that PIP2 regulates KCNQ3 channels through four different domains: 1) the A-B helix linker that we previously identified as important for both KCNQ2 and KCNQ3, 2) the junction between S6 and the A helix, 3) the S2-S3 linker, and 4) the S4-S5 linker. We also found that the apparent strength of PIP2 interactions within any of these domains was not coupled to the voltage dependence of channel activation. Extensive homology modeling and docking simulations with the WT or mutant KCNQ3 channels and PIP2 were consistent with the experimental data. Our results indicate that PIP2 modulates KCNQ3 channel function by interacting synergistically with a minimum of four cytoplasmic domains.

KEYWORDS:

KCNQ; M current; PIP2; ion channel gating; ion channel modulation; lipid signaling; neuroscience; phospholipid; potassium channel; signal transduction; structure-function

PMID:
30348901
PMCID:
PMC6302169
[Available on 2019-12-14]
DOI:
10.1074/jbc.RA118.005401
[Indexed for MEDLINE]

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