Lipid raft microdomains and neurotransmitter signalling

Key Points

  • Lipid rafts are submicroscopic membrane microdomains rich in sphingomyelin and cholesterol.

  • Two common types of lipid raft have been proposed and studied in neurotransmitter signalling: planar lipid rafts (also known as non-caveolar, or glycolipid, rafts) and caveolae.

  • Several classes of neurotransmitter receptors and transporters associate with lipid raft membrane domains and the functional effects of this association are heterogeneous.

  • Lipid rafts are involved in the clustering and trafficking of receptors and transporters, and these rafts seem to be capable of either facilitating or inhibiting neurotransmitter signalling or transport.

  • Cytoskeletal elements such as microtubules or actin microfilaments, and the monomers or dimers that comprise them, associate with lipid rafts and might function to orchestrate neurotransmitter signalling.

  • The localization of signalling components to lipid rafts indicates that molecular events altering this association could contribute to a number of neurological or psychiatric diseases.

  • The heterogeneous action of lipid rafts on neurotransmitter signalling might help to form a uniform hypothesis for the role played by these domains and could help point the way to a mechanism whereby manipulation of rafts generates a pattern of altered information flow.

Abstract

Lipid rafts are specialized structures on the plasma membrane that have an altered lipid composition as well as links to the cytoskeleton. It has been proposed that these structures are membrane domains in which neurotransmitter signalling might occur through a clustering of receptors and components of receptor-activated signalling cascades. The localization of these proteins in lipid rafts, which is affected by the cytoskeleton, also influences the potency and efficacy of neurotransmitter receptors and transporters. The effect of lipid rafts on neurotransmitter signalling has also been implicated in neurological and psychiatric diseases.

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Figure 1: Lipid raft microdomains and membrane organization of neurotransmitter signalling molecules.
Figure 2: Lipid rafts as sites for endocytosis and trafficking of neurotransmitter receptors.
Figure 3: Cytoskeletal and lipid raft organization of neurotransmitter signalling molecules.

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Acknowledgements

This work was supported by research grants from the National Institutes of Health to M.M.R and by a National Institutes of Health Training Grant to J.A.A. and R.H. We thank R. Donati for valuable comments about this manuscript.

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Correspondence to Mark M. Rasenick.

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DATABASES

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Alzheimer's disease

Bipolar affective disorder

Parkinson's disease

Schizophrenia

Unipolar depression

FURTHER INFORMATION

Rasenick's laboratory

Glossary

Triton X-100

A commonly used non-ionic surfactant detergent that solubilizes proteins and cell membranes.

Sucrose density gradient centrifugation

Separation of cell organelles and subcellular components from crude cellular extracts based on their buoyant density.

P2X purinoreceptor

A plasma membrane channel that is activated by the binding of ATP and is permeant to mono- and divalent cations.

Synaptosome

A preparation of elements of the presynaptic and postsynaptic terminal, isolated after subcellular fractionation. Synaptosomes retain some anatomical integrity and can take up, store and release neurotransmitters.

Heparan sulphate proteoglycans

A group of proteoglycans in which heparan sulphate chains are attached near the cell surface or on extracellular matrix proteins. Agrin is one such proteoglycan, named for its involvement in aggregation of acetylcholine receptors during synaptogenesis.

HEK293 cells

A hypotriploid human cell line derived from embryonic kidney epithelial cells; commonly used as an expression system to study signalling and recombinant proteins.

CHO cells

A chinese hamster ovary cell line often used as an expression system for studying cell signalling and recombinant proteins.

Bmax

A measure of the total number of receptors, determined by the binding of agonist or antagonist ligands. This number will reflect either surface receptors or surface plus internalized receptors depending on the chemical characteristics of the ligand.

RNA interference

(RNAi). A molecular method in which small interfering RNA sequences are introduced into cells or tissues, and subsequently silence the expression of target genes.

C6 glioma cells

A diploid rat cell line cloned from a glial tumour.

Palmitoylation

The covalent attachment of a palmitate (16-carbon saturated fatty acid) to a cysteine residue through a thioester bond.

Myristoylation

The covalent (and, in the case of a G protein, cotranslational) attachment of a hydrophobic myristoyl group to the amino-terminal glycine residue of a nascent polypeptide.

Liposome

A lipid vesicle artificially formed by sonicating lipids in an aqueous solution.

Scaffolding proteins

Proteins that organize groups of interacting intracellular signalling proteins into signalling complexes.

Second messengers

Small intracellular signalling molecules generated in large numbers in response to the primary message of a hormone or neurotransmitter.

Calcium wave

A phenomena by which calcium released from intracellular stores diffuses within a cell in a pattern of waves.

Microtubules

Hollow tubes, 25 nm in diameter, formed by the lateral association of 13 protofilaments which are themselves polymers of α- and β-tubulin subunits.

Colchicine

Alkaloid used to inhibit the polymerization of tubulin and cause the depolymerization of microtubules.

Postsynaptic density

An electron-dense thickening underneath the postsynaptic membrane at excitatory synapses that contains receptors, structural proteins linked to the actin cytoskeleton and signalling elements, such as kinases and phosphatases.

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Allen, J., Halverson-Tamboli, R. & Rasenick, M. Lipid raft microdomains and neurotransmitter signalling. Nat Rev Neurosci 8, 128–140 (2007). https://doi.org/10.1038/nrn2059

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