Abstract
Sphingolipids are structural components in the plasma membranes of eukaryotic cells. Their metabolism produces bioactive signaling molecules that modulate fundamental cellular processes. The segregation of sphingolipids into distinct membrane domains is likely essential for cellular function. This review presents the early studies of sphingolipid distribution in the plasma membranes of mammalian cells that shaped the most popular current model of plasma membrane organization. The results of traditional imaging studies of sphingolipid distribution in stimulated and resting cells are described. These data are compared with recent results obtained with advanced imaging techniques, including super-resolution fluorescence detection and high-resolution secondary ion mass spectrometry (SIMS). Emphasis is placed on the new insight into the sphingolipid organization within the plasma membrane that has resulted from the direct imaging of stable isotope-labeled lipids in actual cell membranes with high-resolution SIMS. Super-resolution fluorescence techniques have recently revealed the biophysical behaviors of sphingolipids and the unhindered diffusion of cholesterol analogs in the membranes of living cells are ultimately in contrast to the prevailing hypothetical model of plasma membrane organization. High-resolution SIMS studies also conflicted with the prevailing hypothesis, showing sphingolipids are concentrated in micrometer-scale membrane domains, but cholesterol is evenly distributed within the plasma membrane. Reductions in cellular cholesterol decreased the number of sphingolipid domains in the plasma membrane, whereas disruption of the cytoskeleton eliminated them. In addition, hemagglutinin, a transmembrane protein that is thought to be a putative raft marker, did not cluster within sphingolipid-enriched regions in the plasma membrane. Thus, sphingolipid distribution in the plasma membrane is dependent on the cytoskeleton, but not on favorable interactions with cholesterol or hemagglutinin. The alternate views of plasma membrane organization suggested by these findings are discussed.
Highlights
The plasma membranes of mammalian cells contain many different lipid species, but the distribution of sphingolipids within the plasma membrane and the mechanisms responsible for this organization are of particular interest
Ceramide-rich domains are postulated to exhibit high ordering that enhances the recruitment of GPIanchored proteins, which modulates their interactions with other membrane proteins (Cremesti et al, 2002; Bollinger et al, 2005)
This review focuses on reports that contextualize the development of current models of plasma membrane organization, and the results that that have led some to question or even reject the raft hypothesis (Shaw, 2006; Kenworthy, 2008; Kraft, 2013; Sevcsik and Schütz, 2016; Wüstner et al, 2016)
Summary
The plasma membranes of mammalian cells contain many different lipid species, but the distribution of sphingolipids within the plasma membrane and the mechanisms responsible for this organization are of particular interest. The different subspecies within the sphingolipid family are known to vary in terms of their chemical properties, expression patterns, specific protein binding partners, and specialized functions (Hannun and Bell, 1989; Mutoh et al, 1995; Snook et al, 2006; Yu et al, 2011; Contreras et al, 2012; Fantini and Yahi, 2015; Prasanna et al, 2016). Detergent-resistant membranes isolated from cells later proved to be artificial structures that were not present in vivo (Lichtenberg et al, 2005) This increased the importance of imaging putative raft components, such as sphingolipids and GPI-anchored proteins, within intact cell membranes. Ceramide-rich domains are postulated to exhibit high ordering that enhances the recruitment of GPIanchored proteins, which modulates their interactions with other membrane proteins (Cremesti et al, 2002; Bollinger et al, 2005). The implications of these findings on models of sphingolipid organization in the plasma membrane are discussed
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