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网上购买快乐10分:Lipid transporter TMEM24/C2CD2L is a Ca2+-regulated component of ER–plasma membrane contacts in mammalian neurons
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It is well established that the cross-talk between the plasma membrane (PM) and the endoplasmic reticulum (ER) plays an important role in neuronal signaling. Until recently, this cross-talk was thought to be mediated primarily by soluble second messengers, such as Ca2+ and IP3, although it has long been known that tight appositions between the ER and the PM occur in all cells and are abundant in neurons. Investigations of the proteins that populate these contacts are shedding new light on feedback regulatory mechanisms between the two membranes. The present study identifies the phospholipid transporter TMEM24/C2CD2L as a regulated component of ER–PM contacts in neurons and suggests that lipid transfer between the two bilayers participates in the control of neuronal signaling.
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.
- ?1To whom correspondence may be addressed. Email: or .
?2Present address: Department of Neuroscience, Novartis Institutes for BioMedical Research, Cambridge, MA 02139.
Author contributions: E.W.S., A.G.S., X.B., Y.C., M.M., and P.D.C. designed research; E.W.S., A.G.S., X.B., Y.W., Y.C., and M.M. performed research; E.W.S., A.G.S., X.B., M.M., and P.D.C. analyzed data; and E.W.S., A.G.S., X.B., M.M., and P.D.C. wrote the paper.
Reviewers: T.G., Institute of Psychiatry and Neurosciences of Paris; and M.M.T., Colorado State University.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1820156116/-/DCSupplemental.
Published under the PNAS license.