Spatial and temporal control of signaling through lipid rafts

doi:10.1016/j.conb.2004.08.003

Current Opinion in Neurobiology

Volume 14, Issue 5, October 2004, Pages 542-550

https://doi.org/10.1016/j.conb.2004.08.003 Get rights and content

Sphingolipid- and cholesterol-dependent microdomains (rafts) order proteins at biological membranes and have been implicated in most signaling processes at the cell surface, but the principles and mechanisms through which lipid rafts influence signaling are not well understood. Recent studies have revealed how lipid rafts are rapidly redistributed and assembled locally in response to extracellular signals, and how components of raft-based signaling domains undergo rapid and regulated rearrangements influencing signal quality, duration, and strength. These findings highlight the exquisitely dynamic properties of signaling domains based on lipid rafts, and suggest that processes of raft trafficking and assembly take central roles in mediating spatial and temporal control of signaling.

Introduction

The membrane systems in any type of cell exhibit substantial and specific differences in their lipid compositions. In addition, specific differences exist between the two leaflets of most bilayers, and lipids in individual leaflets are not distributed homogeneously in the plane of the membrane. Mainly because of their distinct biophysical properties, sphingolipids and cholesterol play a predominant part in generating microdomains in biological membranes 1., 2.. These sphingolipid- and cholesterol-dependent microdomains are also designated as lipid rafts. Lipid rafts are first assembled at the Golgi, and take major roles in specific trafficking of proteins and lipids to and from cellular compartments [3]. Different types of cells at distinct developmental stages can differ substantially in their raft contents, and association with lipid rafts influences signaling and the assembly of cellular structures in specific ways [1].

The existence and functional significance of lipid rafts are well established. However, issues such as the molecular nature (e.g. domains versus lipid shells) and half-lives of rafts, as well as the states of assembly of raft-based platforms in situ, have remained controversial 4., 5.. As a consequence, although much progress is being made in elucidating the roles of lipid rafts in cell trafficking and signaling, it is not yet clear how exactly rafts contribute to signaling at the molecular level.

This review focuses on recent developments in our understanding of how lipid rafts influence spatial and temporal control of signaling in neurons. We elaborate on the notion that lipid rafts reflect ordering mechanisms to ensure reliably that defined components come in close vicinity within microdomains of membranes, in specific ways, at defined sites, and at defined times. Because many of the conceptual developments have emerged from studies of non-neuronal cells, we also discuss some of those studies in the review, elaborating on how the results have guided studies of related processes in the nervous system. More in-depth discussions about the nature and roles of lipid rafts in trafficking and signaling, as well as their emerging roles in nervous system diseases such as Alzheimer's and prion diseases, can be found in several recent reviews (for example 1., 2., 6.).

In the following sections we first discuss basic principles of how rafts can influence signaling, and then turn to the ways in which processes of raft recruitment and assembly contribute to spatial and temporal specificity of signaling in neurons.

Section snippets

Signal-induced recruitment and assembly of raft-dependent platforms

Extracellular ligands can initiate raft recruitment and assembly, which in turn can affect the quality, strength, and duration of intracellular signaling. Lipid microdomains are thought to enhance the efficacy and reliability of signaling by concentrating locally selected protein components at specific sites on membranes. This principle is nicely illustrated in T-cell activation, where a requirement for raft association of major histocompatibility complex (MHC) molecules can be bypassed by

Raft association modifies signaling

Raft association influences the strength and quality of signaling through at least two distinct types of mechanisms: first, the activity of signaling molecules can be influenced by the local environment at the raft, and second, signaling molecules can interact with and modify distinct downstream components at and outside of the raft.

In two examples of how the local environment at rafts modifies signaling, first, PSD-95 recruits the voltage-gated channel Kv1.4 to rafts, where channel activity is

Spatial control of signaling through rafts

Recent discoveries of signal-related trafficking, local targeting, and local accumulation of rafts have established lipid rafts as a major factor in spatial control of signaling.

Many of the molecular components regulating the actin cytoskeleton, cell motility, and adhesion are associated with rafts. These include Rho-type GTPases, and the phosphoinositides PtdIns(4,5)P₂ and PtdIns(3,4,5)P₃ [16]. These associations suggested that local accumulation of rafts might mediate some of the spatial

Temporal control of signaling through rafts

Similar to the way lipid rafts are highly dynamic entities, signaling domains based on lipid rafts appear to consist of loosely interconnected and rapidly exchanging signaling modules. These dynamic properties are well suited to couple the processes of domain assembly and disassembly to temporal control in signaling. Although raft disruption often abolishes persistent signaling, stable anchorage to the cortical cytoskeleton or extracellular components tends to prevent recruitment to raft-based

Sustained signaling at synapses

Synapses are the major sites of information transfer, and hence of signaling in the nervous system. Unsurprisingly, the assembly and dynamics of synapses involve raft assembly and trafficking. Synaptogenesis in vitro can be promoted by glia-derived cholesterol in association with apolipoprotein allele E4 (ApoE4) lipoproteins, which suggests that cholesterol-rich lipid rafts could be involved in synapse maturation and/or stability [47]. However, although it is clear that raft accumulation and

Conclusions and future directions

It has become apparent that processes of raft-based domain regulation at the plasma membrane are directly coupled to spatial and temporal control of signaling. Thus, local raft recruitment and raft domain assembly mediate spatial control of signaling in response to extracellular signals. Such raft-mediated polarization plays a central part in directed motility processes such as cell migration, growth cone guidance, and the local interactions of cells with their environment. Likewise, mechanisms

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

The Friedrich Miescher Institut for Biomedical Research is a part of the Novartis research foundation.

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Spatial and temporal control of signaling through lipid rafts

Introduction

Section snippets

Signal-induced recruitment and assembly of raft-dependent platforms

Raft association modifies signaling

Spatial control of signaling through rafts

Temporal control of signaling through rafts

Sustained signaling at synapses

Conclusions and future directions

References and recommended reading

Acknowledgements

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