The fluid mosaic model of Singer and Nicolson (1972) and its subsequent extensions (Simons and Vaz 2004; Jacobson et al. 2007; Kusumi et al. 2005) point to the importance of mobile membrane components and intracellular membrane flow for the proper function of biological cells. Molecular interaction partners, especially those involved in signaling cascades, must diffuse laterally to be able to meet and interact, and thereby initiate chemical reactions (Khan and Pessin 2002; Pierce et al. 2002). Certain membrane-bound receptors (homo- or hetero-) dimerize after ligand binding to become activated. Classical examples are receptor tyrosine kinases such as insulin and EGF receptors (Schlessinger 2000). There are an increasing number of recent reports indicating that seven-transmembrane-helix (7TM) receptors (also named G protein coupled receptors, GPCRs) also form homo- and heterodimers whose functional importance is presently a matter of debate (Bulenger et al. 2005; Chabre and le Maire 2005). The role of diffusing neuroreceptors for development and plasticity of synaptic transmission was demonstrated using single particle imaging by Choquet and Triller (2003).
The fact that the components of biological membranes are heterogeneously distributed in space and time was already noted in the classical fluid mosaic model of Singer and Nicolson. Recent models describe biological membranes as comprising (sub)micrometer-sized lipid assemblies, sometimes termed rafts, which might provide fluid platforms that segregate membrane components, dynamically compartmentalize and enrich, for example, certain proteins and thereby modulate cellular signaling reactions (Simons and Vaz 2004, Jacobson et al. 2007; Kusumi et al. 2005). Compartmentalization in the form of such nano- or microdomains has been proposed to explain the efficiency of signal transduction and amplification at low physiological membrane concentrations of the signaling partners, due to their enrichment in the specialized signaling platforms (Ostrom and Insel 2004). The mobility of the membrane components inside compartments is by definition temporarily restricted, and may be different outside the compartments. The compartments themselves might be mobile or immobile, and might continuously change size and composition. Reliable quantitative data on size, composition, and dynamical changes of such domains, and especially their relevance for biological function in live cells are still very rare.
For example, after activating cellular signaling events, receptors undergo a number of deactivating processes including desensitization, internalization, degradation, or recycling. Mobility might be different in each of these receptor states and particular ligands or ligand classes might have further specific modulating effects. Further complexities are introduced by the interaction of receptors, signaling complexes, and platforms with intracellular proteins structures such as the cytoskeleton, or with components that modulate internalization and degradation pathways.
Although the different processes for signaling appear conceptually very reasonable, there are surprisingly few hard quantitative data available. Single-molecule microscopy and spectroscopy can in this context offer substantial new quantitative information to decipher the complex cellular biochemistries with exceptional spatial and temporal resolution.
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