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Title: Remodeling neuronal ER–PM junctions is a conserved nonconducting function of Kv2 plasma membrane ion channels

Journal Article · · Molecular Biology of the Cell

The endoplasmic reticulum (ER) and plasma membrane (PM) form junctions crucial to ion and lipid signaling and homeostasis. The Kv2.1 ion channel is localized at ER–PM junctions in brain neurons and is unique among PM proteins in its ability to remodel these specialized membrane contact sites. Here, we show that this function is conserved between Kv2.1 and Kv2.2, which differ in their biophysical properties, modulation, and cellular expression. Kv2.2 ER–PM junctions are present at sites deficient in the actin cytoskeleton, and disruption of the actin cytoskeleton affects their spatial organization. Kv2.2-containing ER–PM junctions overlap with those formed by canonical ER–PM tethers. The ability of Kv2 channels to remodel ER–PM junctions is unchanged by point mutations that eliminate their ion conduction but eliminated by point mutations within the Kv2-specific proximal restriction and clustering (PRC) domain that do not impact their ion channel function. The highly conserved PRC domain is sufficient to transfer the ER–PM junction–remodeling function to another PM protein. Last, brain neurons in Kv2 double-knockout mice have altered ER–PM junctions. Together, these findings demonstrate a conserved in vivo function for Kv2 family members in remodeling neuronal ER–PM junctions that is distinct from their canonical role as ion-conducting channels shaping neuronal excitability.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Molecular Foundry
Sponsoring Organization:
USDOE; National Institutes of Health (NIH); American Heart Association (AHA)
Grant/Contract Number:
AC02-05CH11231; NIH R01 NS042225; NIH U01 NS090581; R01 NS096317
OSTI ID:
1625247
Journal Information:
Molecular Biology of the Cell, Vol. 29, Issue 20; ISSN 1059-1524
Publisher:
American Society for Cell BiologyCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 38 works
Citation information provided by
Web of Science

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Unlocking the gating mechanism of Kv2.1 using guangxitoxin journal December 2018
Kv2 channels create endoplasmic reticulum / plasma membrane junctions: a brief history of Kv2 channel subcellular localization journal January 2019
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Axonal Endoplasmic Reticulum Dynamics and Its Roles in Neurodegeneration. text January 2020
A toolbox of nanobodies developed and validated for use as intrabodies and nanoscale immunolabels in mammalian brain neurons journal September 2019
A toolbox of nanobodies developed and validated for use as intrabodies and nanoscale immunolabels in mammalian brain neurons journal September 2019
Sticking With It: ER-PM Membrane Contact Sites as a Coordinating Nexus for Regulating Lipids and Proteins at the Cell Cortex journal July 2020
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Figures / Tables (13)