Transmembrane phospholipid

Bevers, E.M., Comfurius, R, Dekkers, D.W., Harmsma, M. andZwaal, R.F. (1998) Regulatory mechanisms of transmembrane phospholipid distributions and pathophysiological implications of transbilayer lipid scrambling. Lupus 7 (Suppl), S126-S131. 

Nakatani, Y, Yamamoto, M., Diyizou, Y. et al. (1996). Studies on the topography of biomembranes regioselective photolabelling in vesicles with the tandem use of cholesterol and a photoactivable transmembrane phospholipidic probe. Chemistry - a European Journal, 2, 129-38. 

Fujimoto K., Umeda M., and Fujimoto T. 1996. Transmembrane phospholipid distribution revealed by freeze-fracture replica labeling. J Cell Sci 109 2453-2460. 

Maeda, T., Asano, A., Okada, Y., and Ohnishi, S., 1977, Transmembrane phospholipid motions induced by F glycoprotein in hemagglutinating virus of Japan, J. Virol. 21 232. 

Lipid phosphate phosphohydrolases (LPPs), formerly called type 2 phosphatidate phosphohydrolases (PAP-2), catalyse the dephosphorylation of bioactive phospholipids (phosphatidic acid, ceramide-1-phosphate) and lysophospholipids (lysophosphatidic acid, sphingosine-1-phosphate). The substrate selectivity of individual LPPs is broad in contrast to the related sphingosine-1-phosphate phosphatase. LPPs are characterized by a lack of requirement for Mg2+ and insensitivity to N-ethylmaleimide. Three subtypes (LPP-1, LPP-2, LPP-3) have been identified in mammals. These enzymes have six putative transmembrane domains and three highly conserved domains that are characteristic of a phosphatase superfamily. Whether LPPs cleave extracellular mediators or rather have an influence on intracellular lipid phosphate concentrations is still a matter of debate. 

The other activity associated with transmembrane receptors is phospholipase C. Phosphatidyl inositol is a membrane phospholipid that after phosphorylation on the head group is found in the membrane as a phos-photidylinostitol bis phosphate. Phospholipase C cleaves this into a membrane associated diacylglycerol (the lipid part) and inositol trisphosphate (IP3, the soluble part). Both play a later role in elevating the level of the second messenger, Ca2+. 

Another, but less well defined, class of molecules, some of whose members mediate adhesion interaction, is the four-transmembrane domain family, which shares similar hydropathy plots and may have similar dispositions with respect to the phospholipid bilayer, for example the myelin proteolipid proteins, the connexins of gap junctions, the ryanodine receptor and others. 

The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions. The exceptions are instances of synaptic transmission mediated via receptors that contain intrinsic enzymatic activity, such as tyrosine kinase or guanylyl cyclase, or via receptors that form ion channels (see Ch. 10). Heterotrimeric G proteins were first identified, named and characterized by Alfred Gilman, Martin Rodbell and others close to 20 years ago. They consist of three distinct subunits, a, (3 and y. These proteins couple the activation of diverse types of plasmalemma receptor to a variety of intracellular processes. In fact, most types of neurotransmitter and peptide hormone receptor, as well as many cytokine and chemokine receptors, fall into a superfamily of structurally related molecules, termed G-protein-coupled receptors. These receptors are named for the role of G proteins in mediating the varied biological effects of the receptors (see Ch. 10). Consequently, numerous effector proteins are influenced by these heterotrimeric G proteins ion channels adenylyl cyclase phosphodiesterase (PDE) phosphoinositide-specific phospholipase C (PI-PLC), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and phospholipase A2 (PLA2), which catalyzes the hydrolysis of membrane phospholipids to yield arachidonic acid. In addition, these G proteins have been implicated in... 

Excitable membranes maintain and rapidly modulate substantial transmembrane ion gradients in response to stimuli 576 Specific lipid messengers are cleaved from reservoir phospholipids by phospholipases upon activation by various stimuli 576 Phospholipids in synaptic membranes are an important target in seizures, head injury, neurodegenerative diseases and cerebral ischemia 576 Some molecular species of phospholipids in excitable membranes are reservoirs of bioactive lipids that act as messengers 576 Mammalian phospholipids generally contain polyunsaturated fatty acyl chains almost exclusively esterified to the second carbon of glycerol 577... 

It can be seen from Figure 1 that the choline-containing phospholipids, phosphatidylcholine and sphingomyelin are localized predominantly in the outer monolayer of the plasma membrane. The aminophospholipids, conprising phosphatidylethanolamine and phosphatidylserine, by contrast, are enriched in the cytoplasmic leaflet of the membrane (Bretcher, 1972b Rothman and Lenard, 1977 Op den Kamp, 1979). The transmembrane distribution of the minor membrane lipid components has been determined by reaction with lipid-specific antibodies (Gascard et al, 1991) and lipid hydrolases (Biitikofer et al, 1990). Such studies have shown that phosphatidic acid, phosphatidylinositol and phosphatidylinositol-4,5-fc -phosphate all resemble phosphatidylethanolamine in that about 80% of the phospholipids are localized in the cytoplasmic leaflet of the membrane. 

Methods used to demonstrate the existence of membrane phospholipid asymmetry, such as chemical labelling and susceptibility to hydrolysis or modification by phospholipases and other enzymes, are rmsuitable for dynamic studies because the rates of chemical and biochemical reactions are of a different order compared to the transmembrane translocahon of the phospholipids. Indirect methods have therefore been developed to measure the translocation rate which are consequent on the loss of membrane phospholipid asymmetry. Thus time scales appropriate to rates of lipid scrambling under resting conditions or when the forces preserving the asymmetric phospholipid distribution are disturbed can be monitored. Generally the methods rely on detecting the appearance of phosphatidylserine on the surface of cells. Methods of demonstrating Upid translocation in mammalian cells has been the subject of a recent review (Bevers etal., 1999). 

Rauch, C. and Farge, R, 2000, Endocytosis switch controlled by transmembrane osmotic pressure and phospholipid number asymmetry. Biophys. J., 78 3036-3047. 

Kester, M., Simonson, M. S., Mene, P., and Sedor, J. R., 1989, Interleukin-1 generates transmembrane signals from phospholipids through novel pathways in cultured rat mesangial cells. J. Clin. Invest. 83 718-723... 

Table I gives a compilation of the molecular composition of SFV grown in BHK-21 cells, based on the revised weight for the viral particle of 41-42 X 10 daltons (Jacrot et al, 1983). If one assumes that each phospholipid-cholesterol pair takes up a surface area of about 90-100 A (Israelachvili and Mitchell, 1975) and each glycolipid about 55 A (Pascher and Sundell, 1977), then about 80% of the surface area in the bilayer is occupied by the lipids, leaving about 20% for the spanning proteins. This is somewhat more than would be expected if 180 spike proteins span the bilayer, each having two transmembrane a helical segments.

Mimms LT, Zampighi G, Nozaki Y, Tanford C, Reynolds JA. Phospholipid vesicle formation and transmembrane protein incorporation using octyl gluco-side. Biochemistry 1981 20 833. 

In addition to the differences in phospholipid content between microbial and host cell membranes, it has been demonstrated that disparity exists between the transmembrane potentials of both organisms. The transmembrane potential is defined by the proton flux between the inner and outer bilayers of the cytoplasmic membrane and ranges from —90 to —110 mV in normal mammalian cells in contrast to transmembrane potentials of —130 to —150mV for logarithmic phase microbes. The differences in these electrochemical gradients have been postulated to drive the influx of peptides into the cell and thus act as a crucial barrier for defining host defense peptide selectivity. ... 

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