Kv2.1 mediates spatial and functional coupling of L-type calcium channels and ryanodine receptors in mammalian neurons
- University of California, Davis, United States
Abstract
The voltage-gated K+ channel Kv2.1 serves a major structural role in the soma and proximal dendrites of mammalian brain neurons, tethering the plasma membrane (PM) to endoplasmic reticulum (ER). Although Kv2.1 clustering at neuronal ER-PM junctions (EPJs) is tightly regulated and highly conserved, its function remains unclear. By identifying and evaluating proteins in close spatial proximity to Kv2.1-containing EPJs, we discovered that a significant role of Kv2.1 at EPJs is to promote the clustering and functional coupling of PM L-type Ca2+ channels (LTCCs) to ryanodine receptor (RyR) ER Ca2+ release channels. Kv2.1 clustering also unexpectedly enhanced LTCC opening at polarized membrane potentials. This enabled Kv2.1-LTCC-RyR triads to generate localized Ca2+ release events (i.e., Ca2+ sparks) independently of action potentials. Together, these findings uncover a novel mode of LTCC regulation and establish a unique mechanism whereby Kv2.1-associated EPJs provide a molecular platform for localized somatodendritic Ca2+ signals in mammalian brain neurons.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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Author details
L Fernando Santana
Funding
National Institute of Neurological Disorders and Stroke (R21 NS101648)
- James S Trimmer
National Heart, Lung, and Blood Institute (R01 HL144071)
- L Fernando Santana
- James S Trimmer
National Institute of General Medical Sciences (T32 GM007377)
- Michael Kirmiz
National Institute of Neurological Disorders and Stroke (F32 NS108519)
- Nicholas C Vierra
National Institute of Neurological Disorders and Stroke (U01 NS099714)
- James S Trimmer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#20485 and #21265) of the University of California, Davis. All perfusions were performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.
Copyright
© 2019, Vierra et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Kv2.1 mediates spatial and functional coupling of L-type calcium channels and ryanodine receptors in mammalian neurons
eLife 8:e49953.
https://doi.org/10.7554/eLife.49953
