Lipid signaling, broadly defined, refers to any biological signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms (such as monoamine neurotransmission) because lipids can freely diffuse through membranes (see osmosis). One consequence of this is that lipid messengers cannot be stored in vesicles prior to release and so are often biosynthesized "on demand" at their intended site of action. As such, many lipid signaling molecules cannot circulate freely in solution but, rather, exist bound to special carrier proteins in serum. Sphingolipid second messengers Ceramide Ceramide (Cer) can be generated by the breakdown of sphingomyelin (SM) by sphingomyelinases (SMases), which are enzymes that hydrolyze the phosphocholine group from the sphingosine backbone. Alternatively, this sphingosine-derived lipid (sphingolipid) can be synthesized from scratch (de novo) by the enzymes serine palmitoyl transferase (SPT) and ceramide synthase in organelles such as the endoplasmic reticulum (ER) and possibly, in the mitochondria-associated membranes (MAMs) and the perinuclear membranes. Being located in the metabolic hub, ceramide leads to the formation of other sphingolipids, with the C1 hydroxyl (-OH) group as the major site of modification. A sugar can be attached to ceramide (glycosylation) through the action of the enzymes, glucosyl or galactosyl ceramide synthases. Ceramide can also be broken down by enzymes called ceramidases, leading to the formation of sphingosine, Moreover, a phosphate group can be attached to ceramide (phosphorylation) by the enzyme, ceramide kinase. It is also possible to regenerate sphingomyelin from ceramide by accepting a phosphocholine headgroup from phosphatidylcholine (PC) by the action of an enzyme called sphingomyelin synthase. The latter process results in the formation of diacylglycerol (DAG) from PC. Ceramide contains two hydrophobic ("water-fearing") chains and a neutral headgroup. Consequently, it has limited solubility in water and is restricted within the organelle where it was formed. Also, because of its hydrophobic nature, ceramide readily flip-flops across membranes as supported by studies in membrane models and membranes from red blood cells (erythrocytes). However, ceramide can possibly interact with other lipids to form bigger regions called microdomains which restrict its flip-flopping abilities. This could have immense effects on the signaling functions of ceramide because it is known that ceramide generated by acidic SMase enzymes in the outer leaflet of an organelle