Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 12, Pages 5775-5784Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1820156116
Keywords
SMP domain; lipid-transfer protein; potassium channel; extended synaptotagmin; VAP
Categories
Funding
- National Institutes of Health [NS36251, DA018343, DK45735]
- Kavli Foundation
- Human Frontier Science Program long-term postdoctoral fellowship
- NIH [T32 GM007223]
- NIH
- Gruber Science Fellowship
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Close appositions between the endoplasmic reticulum (ER) and the plasma membrane (PM) are a general feature of all cells and are abundant in neurons. A function of these appositions is lipid transport between the two adjacent bilayers via tethering proteins that also contain lipid transport modules. However, little is known about the properties and dynamics of these proteins in neurons. Here we focused on TMEM24/C2CD2L, an ER-localized SMP domain containing phospholipid transporter expressed at high levels in the brain, previously shown to be a component of ER-PM contacts in pancreatic beta-cells. TMEM24 is enriched in neurons versus glial cells and its levels increase in parallel with neuronal differentiation. It populates ER-PM contacts in resting neurons, but elevations of cytosolic Ca2+ mediated by experimental manipulations or spontaneous activity induce its transient redistribution throughout the entire ER. Dissociation of TMEM24 from the plasma membrane is mediated by phosphorylation of an array of sites in the C-terminal region of the protein. These sites are only partially conserved in C2CD2, the paralogue of TMEM24 primarily expressed in nonneuronal tissues, which correspondingly display a much lower sensitivity to Ca2+ elevations. ER-PM contacts in neurons are also sites where Kv2 (the major delayed rectifier K+ channels in brain) and other PM and ER ion channels are concentrated, raising the possibility of a regulatory feedback mechanism between neuronal excitability and lipid exchange between the ER and the PM.
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