The Caveolar Paradox: Suppressing, Inducing, and Terminating eNOS Signaling

It is now established that specialized plasmalemmal lipid microenvironments, termed lipid rafts by Simons and Toomre,1 take part in various signal transduction processes. One subset of lipid rafts (which contain mostly cholesterol and sphingolipids) is found in plasmalemmal vesicles termed caveolae. The term caveolae (“little caves”) was introduced more than 40 years ago to describe plasma membrane invaginations identified by electron microscopy in a wide variety of cell types. Originally, these 50- to 100-nm plasmalemmal vesicles were shown to participate in the transcellular transport of macromolecules (transcytosis) and in the uptake of small molecules (potocytosis).2 However, it is only recently, with the identification of caveolins as the structural coat component of caveolae, that it has been recognized that caveolae are involved in signal transduction by ensuring the compartmentation of signaling molecules, such as G protein and tyrosine kinase–associated receptors, as well as endothelial nitric oxide synthase (eNOS). The identification of such distinct roles raises the question of how the same organelle can participate in these apparently quite different functions simultaneously. However, in the case of eNOS, recent data suggest that both of these functions (ie, as signaling platforms and intracellular trafficking modules) are, in fact, intimately related and complementary.Although both eNOS and caveolins have several consensus sequences that have been proposed to participate in protein-protein interactions, evidence for a functional association between eNOS and caveolins exists only for the caveolin scaffolding domain (CSD), a juxtamembrane region of 20 amino acids in the C-terminal moiety of caveolin.4 Like other modular protein domains, the scaffolding domain of caveolin facilitates the generation of preassembled oligomeric proteins and, in addition, maintains these various signaling proteins in their off state.2 3 4 Note, however, that the presence of a CSD consensus–binding sequence does not necessarily imply that a given protein …