Skip to main content

The Role of Lipid Rafts in Signal Transduction and Synaptic Plasticity of Neural Cells

  • Chapter
Membrane Microdomain Signaling

Abstract

Compartmentalization of proteins within the cell plays a fundamental role in the spatial and temporal organization of intracellular signaling systems. Although protein phosphorylation has long been known to be involved in this process, lipid microdomains enriched in sphingolipids and cholesterol, also known as lipid rafts, have recently been identified as regions within plasma membranes that are important for numerous cellular processes, including signal transduction, membrane trafficking, molecular sorting, and cell adhesion (Harder et al., 1998; Dermine et al., 2001). The unique lipid composition of rafts creates a more ordered lipid environment than is found in the rest of the plasma membrane (Simons and Ikonen, 1997; Brown and London, 2000), conferring to these specialized structures resistance to non-ionic detergent extraction at 4°C using Triton X-100 and giving rise to their alternative name of detergent-resistant membranes (DRMs). However, one should be cautious in assuming that lipid rafts can be isolated in their native state and that the relationship between their operational definition, namely detergent-insolubility at 4°C, flotation at a certain buoyancy, and cholesterol-dependency, fully reflects their state in vivo (for review, see Lai, 2003). A difficulty with the study of lipid rafts is that they may be too small (a few tens to hundreds of nanometers in diameter) (Brown and London, 2000; Abrami et al., 2001; Brown, 2001; Pierini and Maxfield, 2001) and too highly dispersed to be directly observed in unperturbed living cells. However, upon stimulation of raft-inserted receptors or antibody clustering, disperse rafts can aggregate to form large domains of several micrometers (Pierini and Maxfield, 2001), like flotillas (Harder et al., 1998; Brown and London, 2000; Dermine et al., 2001; Pierini and Maxfield, 2001), thereby inducing clustering of membrane components as a prerequisite for signal transduction.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Abrami L., Fivaz M., Kobayashi T., Kinoshita T., Parton R. G., and van der Goot F. G. (2001) Cross-talk between caveolae and glycosylphosphatidylinositol-rich domains. J. Biol. Chem. 276, 30,729–30,736.

    Article  PubMed  CAS  Google Scholar 

  • Anderson R. G. (1998) The caveolae membrane system. Annu. Rev. Biochem. 67, 199–225.

    Article  PubMed  CAS  Google Scholar 

  • Arni S., Keilbaugh S. A., Ostermeyer A. G., and Brown D. A. (1998) Association of GAP-43 with detergent-resistant membranes requires two palmitoylated cysteine residues. J. Biol. Chem. 273, 28,478–28,485.

    Article  PubMed  CAS  Google Scholar 

  • Becher A., White J. H., and McIlhinney R. A. (2001) The gamma-aminobutyric acid receptor B, but not the metabotropic glutamate receptor type-1, associates with lipid rafts in the rat cerebellum. J. Neurochem. 79, 787–795.

    Article  PubMed  CAS  Google Scholar 

  • Braun J. E. and Madison D. V. (2000) A novel SNAP25-caveolin complex correlates with the onset of persistent synaptic potentiation. J. Neurosci. 20, 5997–6006.

    PubMed  CAS  Google Scholar 

  • Brown D. A. (2001) Seeing is believing: visualization of rafts in model membranes. Proc. Natl. Acad. Sci. USA 98, 10,517–10,518.

    Article  PubMed  CAS  Google Scholar 

  • Brown D. A. and London E. (1998) Functions of lipid rafts in biological membranes. Annu. Rev. Cell Dev. Biol. 14, 111–136.

    Article  PubMed  CAS  Google Scholar 

  • Brown D. A. and London E. (2000) Structure and function of sphingolipid-and cholesterol-rich membrane rafts. J. Biol. Chem. 275, 17,221–17,224.

    Article  PubMed  CAS  Google Scholar 

  • Bruckner K., Pasquale E. B., and Klein R. (1997) Tyrosine phosphorylation of transmembrane ligands for Eph receptors. Science 275, 1640–1643.

    Article  PubMed  CAS  Google Scholar 

  • Bruses J. L., Chauvet N., and Rutishauser U. (2001) Membrane lipid rafts are necessary for the maintenance of the (alpha)7 nicotinic acetylcholine receptor in somatic spines of ciliary neurons. J. Neurosci. 21, 504–512.

    PubMed  CAS  Google Scholar 

  • Cavallaro U., Niedermeyer J., Fuxa M., and Christofori G. (2001) N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signaling. Nat. Cell Biol. 3, 650–657.

    Article  PubMed  CAS  Google Scholar 

  • Chamberlain L. H., Burgoyne R. D., and Gould G. W. (2001) SNARE proteins are highly enriched in lipid rafts in PC12 cells: implications for the spatial control of exocytosis. Proc. Natl. Acad. Sci. USA 98, 5619–5624.

    Article  PubMed  CAS  Google Scholar 

  • Craven S. E., El-Husseini A. E., and Bredt D. S. (1999) Synaptic targeting of the postsynaptic density protein PSD-95 mediated by lipid and protein motifs. Neuron 22, 497–509.

    Article  PubMed  CAS  Google Scholar 

  • Crossin K. L. and Krushel L. A. (2000) Cellular signaling by neural cell adhesion molecules of the immunoglobulin superfamily. Dev. Dyn. 218, 260–279.

    Article  PubMed  CAS  Google Scholar 

  • Delling M., Wischmeyer E., Dityatev A., Sytnyk V., Veh R. W., Karschin A., et al. (2002) The neural cell adhesion molecule regulates cell-surface delivery of G-protein-activated inwardly rectifying potassium channels via lipid rafts. J. Neurosci. 22, 7154–7164.

    PubMed  CAS  Google Scholar 

  • Dermine J. F., Duclos S., Garin J., St-Louis F., Rea S., Parton R. G., et al. (2001) Flotillin-1-enriched lipid raft domains accumulate on maturing phagosomes. J. Biol. Chem. 276, 18,507–18,512.

    Article  PubMed  CAS  Google Scholar 

  • Doherty P., Smith P., and Walsh F. S. (1996) Shared cell adhesion molecule (CAM) homology domains point to CAMs signaling via FGF receptors. Perspect. Dev. Neurobiol. 4, 157–168.

    PubMed  CAS  Google Scholar 

  • Doherty P. and Walsh F. S. (1996) CAM-FGF receptor interactions: a model for axonal growth. Mol. Cell. Neurosci. 8, 99–111.

    Article  CAS  Google Scholar 

  • Drake C. T., Bausch S. B., Milner T. A., and Chavkin C. (1997) GIRK1 immunoreactivity is present predominantly in dendrites, dendritic spines, and somata in the CA1 region of the hippocampus. Proc. Natl. Acad. Sci. USA 94, 1007–1012.

    Article  PubMed  CAS  Google Scholar 

  • El-Husseini Ael D., Craven S. E., Brock S. C., and Bredt D. S. (2001) Polarized targeting of peripheral membrane proteins in neurons. J. Biol. Chem. 276, 44,984–44,992.

    Article  Google Scholar 

  • Faivre-Sarrailh C., Gauthier F., Denisenko-Nehrbass N., Le Bivic A., Rougon G., and Girault J. A. (2000) The glycosylphosphatidyl inositol-anchored adhesion molecule F3/contactin is required for surface transport of paranodin/contactin-associated protein (caspr). J. Cell Biol. 149, 491–502.

    Article  PubMed  CAS  Google Scholar 

  • Fragoso R., Ren D., Zhang X., Su M. W., Burakoff S. J., and Jin Y. J. (2003) Lipid raft distribution of CD4 depends on its palmitoylation and association with Lck, and evidence for CD4-induced lipid raft aggregation as an additional mechanism to enhance CD3 signaling. J. Immunol. 170, 913–921.

    PubMed  CAS  Google Scholar 

  • Gonzalo S. and Linder M. E. (1998) SNAP-25 palmitoylation and plasma membrane targeting require a functional secretory pathway. Mol. Biol. Cell 9, 585–597.

    PubMed  CAS  Google Scholar 

  • Goslin K., Schreyer D. J., Skene J. H., and Banker G. (1990) Changes in the distribution of GAP-43 during the development of neuronal polarity. J. Neurosci. 10, 588–602.

    PubMed  CAS  Google Scholar 

  • Guzzi F., Zanchetta D., Chini B., and Parenti M. (2001) Thioacylation is required for targeting G-protein subunit G(o1alpha) to detergent-insoluble caveolin-containing membrane domains. Biochem. J. 355, 323–331.

    Article  PubMed  CAS  Google Scholar 

  • Harder T., Scheiffele P., Verkade P., and Simons K. (1998) Lipid domain structure of the plasma membrane revealed by patching of membrane components. J. Cell Biol. 141, 929–942.

    Article  PubMed  CAS  Google Scholar 

  • He Q. and Meiri K. F. (2002) Isolation and characterization of detergent-resistant microdomains responsive to NCAM-mediated signaling from growth cones. Mol. Cell. Neurosci. 19, 18–31.

    Article  PubMed  CAS  Google Scholar 

  • Henke R. C., Seeto G. S., and Jeffrey P. L. (1997) Thy-1 and AvGp50 signal transduction complex in the avian nervous system: c-Fyn and G alpha i protein association and activation of signaling pathways. J. Neurosci. Res. 49, 655–670.

    Article  PubMed  CAS  Google Scholar 

  • Hess D. T., Patterson S. I., Smith D. S., and Skene J. H. (1993) Neuronal growth cone collapse and inhibition of protein fatty acylation by nitric oxide. Nature 366, 562–565.

    Article  PubMed  CAS  Google Scholar 

  • Kasahara K., Watanabe K., Takeuchi K., Kaneko H., Oohira A., Yamamoto T., et al. (2000) Involvement of gangliosides in glycosylphosphatidylinositol-anchored neuronal cell adhesion molecule TAG-1 signaling in lipid rafts. J. Biol. Chem. 275, 34,701–34,709.

    Article  PubMed  CAS  Google Scholar 

  • Kramer E. M., Klein C., Koch T., Boytinck M., and Trotter J. (1999) Compartmentation of Fyn kinase with glycosylphosphatidylinositol-anchored molecules in oligodendrocytes facilitates kinase activation during myelination. J. Biol. Chem. 274, 29,042–29,049.

    Article  PubMed  CAS  Google Scholar 

  • Lai E. C. (2003) Lipid rafts make for slippery platforms. J. Cell Biol. 162, 365–370.

    Article  PubMed  CAS  Google Scholar 

  • Lang T., Bruns D., Wenzel D., Riedel D., Holroyd P., Thiele C., et al. (2001) SNAREs are concentrated in cholesterol-dependent clusters that define docking and fusion sites for exocytosis. EMBO J. 20, 2202–2213.

    Article  PubMed  CAS  Google Scholar 

  • Ledesma M. D., Simons K., and Dotti C. G. (1998) Neuronal polarity: essential role of protein-lipid complexes in axonal sorting. Proc. Natl. Acad. Sci. USA 95, 3966–3971.

    Article  PubMed  CAS  Google Scholar 

  • Liang X., Nazarian A., Erdjument-Bromage H., Bornmann W., Tempst P., and Resh M. D. (2001) Heterogeneous fatty acylation of Src family kinases with polyunsaturated fatty acids regulates raft localization and signal transduction. J. Biol. Chem. 276, 30,987–30,994.

    Article  PubMed  CAS  Google Scholar 

  • Little E. B., Edelman G. M., and Cunningham B. A. (1998) Palmitoylation of the cytoplasmic domain of the neural cell adhesion molecule N-CAM serves as an anchor to cellular membranes. Cell Adhes. Commun. 6, 415–430.

    Article  PubMed  CAS  Google Scholar 

  • Liu Y. C., Chapman E. R., and Storm D. R. (1991) Targeting of neuromodulin (GAP-43) fusion proteins to growth cones in cultured rat embryonic neurons. Neuron 6, 411–420.

    Article  PubMed  CAS  Google Scholar 

  • Martens J. R., Navarro-Polanco R., Coppock E. A., Nishiyama A., Parshley L., Grobaski T. D., et al. (2000) Differential targeting of Shaker-like potassium channels to lipid rafts. J. Biol. Chem. 275, 7443–7446.

    Article  PubMed  CAS  Google Scholar 

  • Naslavsky N., Stein R., Yanai A., Friedlander G., and Taraboulos A. (1997) Characterization of detergent-insoluble complexes containing the cellular prion protein and its scrapie isoform. J. Biol. Chem. 272, 6324–6331.

    Article  PubMed  CAS  Google Scholar 

  • Niethammer P., Delling M., Sytnyk V., Dityatev A., Fukami K., and Schachner M. (2002) Cosignaling of NCAM via lipid rafts and the FGF receptor is required for neuritogenesis. J. Cell Biol. 157, 521–532.

    Article  PubMed  CAS  Google Scholar 

  • Paratcha G., Ledda F., and Ibanez C. F. (2003) The neural cell adhesion molecule NCAM is an alternative signaling receptor for GDNF family ligands. Cell 113, 867–879.

    Article  PubMed  CAS  Google Scholar 

  • Parolini I., Topa S., Sorice M., Pace A., Ceddia P., Montesoro E., et al. (1999) Phorbol ester-induced disruption of the CD4-Lck complex occurs within a detergent-resistant microdomain of the plasma membrane. Involvement of the translocation of activated protein kinase C isoforms. J. Biol. Chem. 274, 14,176–14,187.

    Article  PubMed  CAS  Google Scholar 

  • Patterson S. I. (2002) Posttranslational protein S-palmitoylation and the compartmentalization of signaling molecules in neurons. Biol. Res. 35, 139–150.

    Article  PubMed  CAS  Google Scholar 

  • Patterson S. I. and Skene J. H. (1994) Novel inhibitory action of tunicamycin homologues suggests a role for dynamic protein fatty acylation in growth cone-mediated neurite extension. J. Cell Biol. 124, 521–536.

    Article  PubMed  CAS  Google Scholar 

  • Pierini L. M. and Maxfield F. R. (2001) Flotillas of lipid rafts fore and aft. Proc. Natl. Acad. Sci. USA 98, 9471–9473.

    Article  PubMed  CAS  Google Scholar 

  • Poteryaev D., Titievsky A., Sun Y. F., Thomas-Crusells J., Lindahl M., Billaud M., et al. (1999) GDNF triggers a novel ret-independent Src kinase family-coupled signaling via a GPI-linked GDNF receptor alpha1. FEBS Lett. 463, 63–66.

    Article  PubMed  CAS  Google Scholar 

  • Schachner M. (1997) Neural recognition molecules and synaptic plasticity. Curr. Opin. Cell Biol. 9, 627–634.

    Article  PubMed  CAS  Google Scholar 

  • Simons K. and Ikonen E. (1997) Functional rafts in cell membranes. Nature 387, 569–572.

    Article  PubMed  CAS  Google Scholar 

  • Simons K. and Toomre D. (2000) Lipid rafts and signal transduction. Nat. Rev. Mol. Cell Biol. 1, 31–39.

    Article  PubMed  CAS  Google Scholar 

  • Smart E. J., Graf G. A., McNiven M. A., Sessa W. C., Engelman J. A., Scherer P. E., et al. (1999) Caveolins, liquid-ordered domains, and signal transduction. Mol. Cell. Biol. 19, 7289–7304.

    PubMed  CAS  Google Scholar 

  • Stefanova I., Horejsi V., Ansotegui I. J., Knapp W., and Stockinger H. (1991) GPI-anchored cell-surface molecules complexed to protein tyrosine kinases. Science 254, 1016–1019.

    Article  PubMed  CAS  Google Scholar 

  • Tansey M. G., Baloh R. H., Milbrandt J., and Johnson E. M. Jr. (2000) GFRalpha-mediated localization of RET to lipid rafts is required for effective downstream signaling, differentiation, and neuronal survival. Neuron 25, 611–623.

    Article  PubMed  CAS  Google Scholar 

  • Trupp M., Scott R., Whittemore S. R., and Ibanez C. F. (1999) Ret-dependent and-independent mechanisms of glial cell line-derived neurotrophic factor signaling in neuronal cells. J. Biol. Chem. 274, 20,885–20,894.

    Article  PubMed  CAS  Google Scholar 

  • Van Vactor D. (1999) Axon guidance. Curr. Biol. 9, R797–R799.

    Article  PubMed  Google Scholar 

  • van’t Hof W. and Resh M. D. (1997) Rapid plasma membrane anchoring of newly synthesized p59fyn: Selective requirement for NH2-terminal myristoylation and palmitoylation at cysteine-3. J. Cell Biol. 136, 1023–1035.

    Article  PubMed  CAS  Google Scholar 

  • Walsh F. S. and Doherty P. (1997) Neural cell adhesion molecules of the immunoglobulin superfamily: role in axon growth and guidance. Annu. Rev. Cell Dev. Biol. 13, 425–456.

    Article  PubMed  CAS  Google Scholar 

  • Winckler B. and Mellman I. (1999) Neuronal polarity: controlling the sorting and diffusion of membrane components. Neuron 23, 637–640.

    Article  PubMed  CAS  Google Scholar 

  • Wu C., Butz S., Ying Y., and Anderson R. G. (1997) Tyrosine kinase receptors concentrated in caveolae-like domains from neuronal plasma membrane. J. Biol. Chem. 272, 3554–3559.

    Article  PubMed  CAS  Google Scholar 

  • Zacharias D. A., Violin J. D., Newton A. C., and Tsien R. Y. (2002) Partitioning of lipid-modified monomeric GFPs into membrane microdomains of live cells. Science 296, 913–916.

    Article  PubMed  CAS  Google Scholar 

  • Zeng L., D’Alessandri L., Kalousek M. B., Vaughan L., and Pallen C. J. (1999) Protein tyrosine phosphatase alpha (PTPalpha) and contactin form a novel neuronal receptor complex linked to the intracellular tyrosine kinase fyn. J. Cell Biol. 147, 707–714.

    Article  PubMed  CAS  Google Scholar 

  • Zhang W., Trible R. P., and Samelson L. E. (1998) LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation. Immunity 9, 239–246.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2005 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Delling, M., Schachner, M. (2005). The Role of Lipid Rafts in Signal Transduction and Synaptic Plasticity of Neural Cells. In: Mattson, M.P. (eds) Membrane Microdomain Signaling. Humana Press. https://doi.org/10.1385/1-59259-803-X:113

Download citation

Publish with us

Policies and ethics