Update articleLipid rafts at postsynaptic sites: distribution, function and linkage to postsynaptic density
Section snippets
Two types of lipid microdomains: caveolae and non-caveolar lipid rafts
Plasma membranes are not homogeneous in structure, even in lipid composition. A number of small microdomains with high cholesterol and sphingolipid content are distributed in the plasma membrane, and these microdomains are essential for various physiological cell functions. These lipid microdomains are called caveolae or lipid rafts (non-caveolar lipid microdomain). Both caveolae and lipid rafts are enriched with sphingolipid and cholesterol (Simons and Ikonen, 1997). Lipid rafts do not have a
Caveolae and caveolins in the brain
There had been conflicting reports about the presence of caveolae and caveolin in neurons until recently (Lang et al., 1998). One group reported that no mRNA species for caveolins had been detected in the brain or neurons, although caveolae have been observed in neuronal membranes by electron microscopy (Bickel et al., 1997, Galbiati et al., 1998). Neurons and neuroblastoma cells apparently do not express caveolin and do not exhibit caveolae, although some studies found caveolae in
Possible function of lipid rafts
Lipid rafts have been implicated in numerous cellular processes including signal transduction, membrane trafficking, cell adhesion, and molecular sorting (Harder et al., 1998, Dermine et al., 2001). A number of molecules involved in cellular signal processing are enriched in lipid rafts (Smart et al., 1999). Lipid rafts may also serve as docking sites for certain extracellular ligands (Brown and London, 2000). Roles for regulated exocytosis and membrane fusion are supported by the findings that
Intracellular distribution of lipid microdomains suggests their roles
Lipid rafts are difficult to see at the light microscopic level without clustering (Brown and London, 2000). Lipid rafts may be too small to see, but clustering might cause lipid rafts to coalesce into larger units. Lipid rafts do not exist constitutively, but clustering of components induces raft formation (Brown and London, 2000). Indeed, lipid raft proteins, often uniformly distributed on the cell surface, can come together and produce clustering with cross-linking treatment by antibodies or
Flotillin appears to be a scaffold protein of non-caveolar lipid rafts
Flotillins, also called cavatellins (Smart et al., 1999, Volonté et al., 1999) were suggested to be functional homologs of caveolins, the caveolar scaffold proteins (Okamoto et al., 1998, Smart et al., 1999), and could be a good marker of non-caveolar lipid rafts in brain (Smart et al., 1999, Volonté et al., 1999), although they are not brain-specific. Flotillin-1 possesses a hydrophobic N-terminal region and is predicted to form a single, outside to inside, transmembrane domain (Edgar and
Presence of postsynaptic lipid rafts and their possible roles for membrane trafficking
Caveolae and non-caveolar lipid rafts (Chamberlain et al., 2001) can be isolated as detergent-insoluble low-density materials and the preparations have been called caveolae Fr, lipid raft Fr, TIFF, detergent-insoluble glycolipid-enriched membranes or detergent-resistant membranes (Brown and London, 2000). Upon treatment of tissues or cells with Triton X-100, membranes are disrupted and various lipid microdomains including caveolae and non-caveolar lipid rafts are fused to each other (Fujimoto
Possible interactions between postsynaptic lipid rafts and PSD
It could be expected that lipid rafts might also occur on the plasma membrane in and around the synaptic active zone, although our immunohistochemical study using anti-flotillin-1 antibody did not clarify this point (Fig. 2). Very small and highly dispersed lipid rafts on the plasma membrane under unstimulated conditions may coalesce into larger platforms, and recruit downstream effector molecules, some of which may be associated with or released from the PSD. The coalesced lipid rafts may even
Molecules connecting the components of postsynaptic lipid rafts and the PSD
Interaction of the postsynaptic lipid rafts and the PSD could be substantiated by the presence of the molecules that connect the two compartments at the postsynaptic sites.
A recent study (Kimura et al., 2001) reported that molecules containing Sorbin homology (SoHo) domain can interact with flotillin, a possible scaffold protein for lipid rafts (see above). Interaction of the SoHo domain-containing proteins with lipid rafts was shown for c-cbl-associated protein (CAP) (also called ponsin) (
Concluding remarks
We presented recent findings supporting the idea that lipid rafts also occur in postsynaptic sites of neurons. The study of synaptic lipid rafts has only recently started and information on it is quite limited. However, the presence of synaptic lipid rafts is highly possible and the microdomain may well play important roles for the maintenance of postsynaptic structures and their regulatory function. Future studies should clearly depict the postsynaptic machinery composed of PSD and the
Acknowledgements
Author greatly appreciates Dr Philip Siekevitz (Rockefeller University, NY) and Dr Shinji Yokoyama (Nagoya City University Medical School, Nagoya, Japan) for their review of the manuscript and encouragement. This research was supported in part by a Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Science and Culture, Toyota Physical and Chemical Research Institute, Uehara Memorial Foundation, and Joint Research Project under the Japan–Korea Basic Scientific
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