Polar Lipid Synthesis

Lipids: Role in Signaling

1st messenger (hormone, neurotransmitter, growth factor, etc.) 2nd messenger (calcium, cAMP, IP3, DAG, ceramide) Signal amplification Modulator ( G protein, receptor tyrosine kinase) Enzyme activation (phospholipases, adenylate cyclase) Enzyme activation (PKA, PKC, phosphatases) substrates

Discovery of the "phospholipid effect" by Hokin MR et al. : phosphorus incorporation into phospholipids showed a remarkable increase in pigeon pancreas slices on stimulation with acetylcholine (J Biol Chem 1953, 203, 967). Michell RH in a famous review proposed for the first time that the "phosphoinositide effect” discovered in 1953 by Hokin plays a role in cellular calcium mobilization (Biochim Biophys Acta 1975, 415, 81) Univ. of Birmingham, UK

Rates of lipid flip-flop across bilayers Diacylgycerol0.1 sec Ceramide10 min Phosphatdiylcholine10 hr Lysophosphatidic acid>10 hr Ganglioside>>10 hr Conclusion: as the headgroup becomes more polar or larger and as the hydrophobic moiety becomes smaller, the lipid flips less readily

ceramide Ceramide-activated protein phosphatase (PP2A, PP1) Ceramide-activated protein kinase Protein kinase C zeta Rb dephosphorylation Growth arrestinflammation ? ? ?

Lipids as receptor agonists – Platelet-activating factor – Lysophosphatidic acid – Sphingosine phosphate – Lipopolysaccharide

Platelet-activating factor (PAF) or 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine – an ether analogue of phosphatidylcholine – causes aggregation of platelets at picomolar concentrations – acts through a G-protein coupled receptor

Model of G-protein coupled receptor (PAF receptor) signal transduction

Lysophosphatidic acid or 1-acyl-sn-glycerol-3-phosphate (LPA) –metabolite of phosphatidic acid –is an important serum mitogen –acts through the EDG family of G-protein coupled receptors

Sphingosine phosphate –Synthesized by sphingosine kinase –Acts through the EDG family of G protein coupled receptors –Also considered to be mitogenic

Bacterial cell wall organization