PI is synthesized from free inositol and CDP-DAG, as shown in Figure 17.5. PI is an unusual phospholipid in that it most frequently contains stearic acid on carbon 1 and arachidonic acid on carbon 2 of the glycerol. Therefore, PI serves as a reservoir of arachidonic acid in membranes and, thus, provides the substrate for prostaglandin (see p. 213) synthesis when required. Like PS, PI has a net negative charge. [Note: There is asymmetry in the phospholipid composition of the cell membrane. PS and PI, for example, are found primarily on the inner leaflet. Asymmetry is achieved by ATP-dependent enzymes known as “flippases” and “floppases.”] 1. Role in signal transduction across membranes: The phosphorylation of membrane-bound PI produces polyphosphoinositides such as phosphatidylinositol 4,5-bisphosphate ([PIP2]; Fig. 17.7). The cleavage of PIP2 by phospholipase C occurs in response to the binding of various neurotransmitters, hormones, and growth factors to G protein–coupled receptors (GPCR), such as the α1 adrenergic receptor, on the cell membrane and activation of the Gq α-subunit (Fig. 17.8). The products of this cleavage, inositol 1,4,5-trisphosphate (IP3) and DAG, mediate the mobilization of intracellular calcium and the activation of protein kinase
C, which act synergistically to evoke specific cellular responses. Signal transduction across the membrane is, thus, accomplished.
2. Role in membrane protein anchoring: Specific proteins can be covalently attached through a carbohydrate bridge to membrane-bound PI (Fig. 17.9). For example, lipoprotein lipase, an enzyme that degrades triacylglycerol in lipoprotein particles (see p. 228), is attached to capillary endothelial cells by a glycosyl phosphatidylinositol (GPI) anchor. [Note: GPI-linked proteins are also found in a variety of parasitic protozoans, such as trypanosomes and leishmania.] Being attached to a membrane lipid (rather than being an integral part of the membrane) allows GPI-anchored proteins increased lateral mobility on the extracellular surface of the plasma membrane. The protein can be cleaved from its anchor by the action of phospholipase C (see Fig. 17.9). [Note: A deficiency in the synthesis of GPI in hematopoietic cells results in the hemolytic disease paroxysmal nocturnal hemoglobinuria, because GPI-anchored proteins protect blood cells from complement-mediated lysis.]
E. Phosphatidylglycerol and cardiolipin
Phosphatidylglycerol occurs in relatively large amounts in mitochondrial membranes and is a precursor of cardiolipin (diphosphatidyglycerol). It is synthesized from CDP-DAG and glycerol 3-phosphate. Cardiolipin (see Fig. 17.2) is synthesized by the transfer of DAG 3-phosphate from CDPDAG to a pre-existing molecule of phosphatidylglycerol.
F. Sphingomyelin