Lipid transporter TMEM24/C2CD2L is a Ca2+-regulated component of ER-plasma membrane contacts in mammalian neurons

Proc Natl Acad Sci U S A. 2019 Mar 19;116(12):5775-5784. doi: 10.1073/pnas.1820156116. Epub 2019 Feb 28.

Abstract

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 β-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.

Keywords: SMP domain; VAP; extended synaptotagmin; lipid-transfer protein; potassium channel.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Channels / metabolism
  • Calcium Signaling / physiology*
  • Cell Line
  • Cell Membrane / metabolism
  • Endoplasmic Reticulum / metabolism
  • Humans
  • Lipids
  • Mammals / metabolism
  • Membrane Proteins / metabolism*
  • Membrane Proteins / physiology
  • Mice
  • Neurons / metabolism
  • Neurons / physiology*
  • Phospholipids / metabolism
  • Phosphorylation
  • Primary Cell Culture
  • Synaptotagmins / metabolism

Substances

  • C2CD2L protein, human
  • C2cd2l protein, mouse
  • Calcium Channels
  • Lipids
  • Membrane Proteins
  • Phospholipids
  • Synaptotagmins
  • Calcium