Specialized Plasma Membrane Compartments Membrane Lipid Rafts vs Caveolae

Membrane/lipid rafts are defined by their enrichment in cholesterol and other lipids, including glycosphingolipids, in the outer leaflet of the lipid bilayer of the plasma membrane. This specialized lipid composition creates membrane regions that have greater order and less fluidity than more disordered portions with less densely packed phospholipids (Pike 2003). Membrane/lipid rafts are found in virtually every eukaryotic cell, but cannot be readily visualized by either light or electron microscopy. Accordingly, some believe their existence is more operational than anatomic (Carver and Schnitzer 2003; Munro 2003). A recent, consensus definition replaced the name "lipid rafts" with "membrane rafts" and defined them as "small (10-200 nm), heterogeneous, highly dynamic, sterol- and sphingolipid-enriched domains that compartmentalize cellular processes," noting that caveolae are a subset of membrane rafts (Pike 2006). Precise information about the biology of membrane rafts (the term that we shall use throughout the remainder of this review) remains limited, in part because of the limitations of techniques available for their study (Helms and Zurzolo 2004; Jacobson et al. 2007).

A challenge in defining the biological role of membrane rafts derives from the lack of universally accepted methods for their isolation and, as a result, controversies with respect to their expression and properties (Carver and Schnitzer 2003; Jacobson et al. 2007; Lucero and Robbins 2004; Munro 2003; Pike 2003, 2004). Nevertheless, substantial data support the existence of membrane rafts and have contributed to important revisions in ideas regarding the organization of plasma membrane components. Older models of membrane organization hypothesized a lipid "sea" with protein "islands" (e.g., the fluid mosaic model, Singer and Nicolson 1972) and that required the collision of protein components ("collision coupling," Bergman and Hechter 1978) to facilitate biochemical reactions, including signal transduction events. Such notions have been modified to accommodate findings that imply an organization of the plasma membrane with co-localization of signaling components (Marguet et al. 2006). Co-localization in lipid microdomains helps explain the efficiency of certain biochemical events (e.g., signal transduction by GPCR) that occur in the plasma membrane environment and that might otherwise be constrained by both the low concentration and relative inaccessibility of reactants.

Unlike the virtually ubiquitous expression of membrane rafts in eukaryotic cells, many cell types (with certain exceptions, e.g., erythrocytes, lymphocytes and neurons) also express caveolae. Caveolae were first identified by electron microscopy as ~100-nm invaginations of the plasma membrane (Palade 1953; Yamada 1955). Caveolae have a lipid composition similar to that of membrane rafts, but in addition, caveolae possess other proteins, including an organelle-specific, structural protein, caveolin (Kurzchalia et al. 1992; Rothberg et al. 1992) and more recently identified, cavin (Hill et al. 2008; Liu and Pilch 2008). As a molecular tag for caveolae, caveolin facilitates biochemical, cell and molecular biological and pharmacological analyses of caveolar microdomains, as well as contributing to the functions of caveolae

(Cohen et al. 2004; Liu et al. 2002; Morris et al. 2004; Ostrom and Insel 2004; van Deurs et al. 2003). Other proteins may also be uniquely expressed in caveolae. One example is flotillins/reggies, but since they are also found in cells that lack caveolae and in non-caveolar membranes, flotillins/reggies cannot be considered "caveo-lae-specific" proteins (Lucero and Robbins 2004). The three known caveolins, caveolin-1, -2 and -3, have a similar overall structure, but differ in primary sequence and tissue expression (van Deurs et al. 2003). An important feature of caveolin-3 is its unique expression in myocytes, in particular skeletal and cardiac myocytes. A large number of studies that have been published regarding caveolins involve the use of biochemical and cell biological approaches, or in recent years, analyses of mice in which each caveolin has been knocked out; results of such studies indicate that the three caveolins are non-identical in their ability to regulate enzymatic and other functional activities (Cohen et al. 2004; Insel and Patel 2007; van Deurs et al. 2003).

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