Membranes phosphoinositides

Since aminoglycoside complexes with membrane phosphoinositides are extremely stable, they could well exist in an intracellular environment with concentrations of aminoglycosides that are achieved in chemotherapeutic treatment. 

Drbak, B.K., Watkins, P.A.C., Valenta, R., Dove, S.K., Lloyd, C.W., Staiger, C.J., 1994, Inhibition of plant plasma membrane phosphoinositide phospholipase C by the actin-binding protein, profilin. Plant J. 6 389—400. 

McLaughlin S, Murray D. Plasma membrane phosphoinositide organization by protein electrostatics. Nature 2005 438 605-611. 

B. Mechanism of Action The mechanism of action of lithium is not well defined. The drug inhibits the recycling of neuronal membrane phosphoinositides involved in the generation of inositol trisphosphate (IP3) and diacylglycerol (DAG). These second messengers are important in amine neurotransmission, including that mediated by central adrenoceptors and muscarinic receptors (Figure 29-2). 

There are actually no data demonstrating that PGE, acting via a receptor coupled to Np or a functionally related N protein, can cause the turnover of membrane phosphoinositides and subsequent Ca " mobilization. However, there is circumstantial evidence which can be interpreted as suggesting that... 

Camper N, Shapiro MS (2007) Regulation of ion transport proteins by membrane phosphoinositides. Nat Rev Neurosci 8 921-934. 

In 1953, Hokin and Hokin reported that the application of acetylcholine to pigeon pancreatic tissue slices resulted in a rapid incorporation of radioactive [32p]orthophosphate into membrane phosphoinositides and phosphatidic acid (Hokin and Hokin, 1953). From these observations they hypothesized that the effect of acetylcholine was due to the rapid degradation and resynthesis... 

Akt is activated by binding of plasma membrane phospholipids downstream of insulin receptors, growth and survival factor receptors in a phosphoinositide 3-kinases dependent manner. In humans, there are three genes in the Akt family Aktl, Akt2 and Akt3. Their respective fimctions are still under investigation. 

All phosphoinositides are found in the cytosolic half of the lipid bilayer of the plasma or intracellular compartment membranes (left part). The different kinases acting on phosphoinositides in mammalian cells are shown in solid lines and the phosphoinositide 3-kinases, in bold. The phosphoinositides counterpart pathways catalysed by known phosphatases are represented by dashed lines. The best known phosphatases are PTEN (Phosphatase and tensin homolog deleted on chromosome 10) and SHIP (SH2 domain-containing inositol 5-phosphatase). 

Pleckstrin homology domain (PH-domain) was first identified at the amino and carboxyl termini of a haematopoietic protein called pleckstrin. PH-domain, a protein region of approximately 120 amino acids, by binding to phosphatidylinositol lipids of the biological membranes induces the translocation of the PH-domain containing protein to membrane compartment. Various PH-domains possess specificities for phosphoinositides phosphorylated at different sites within the inositol ring. 

PH Pleckstrin homology domain Binding to membrane phospholipids, such as phosphoinositides... 

The current understanding on activation of Tec kinases fits into a two-step model. In the first step an intramolecular interaction between the SH3 domain and aproline-rich region in the TH domain is disrupted by binding ofthe PH domain to phosphoinositides, G protein subunits, or the FERM domain of Fak. These interactions lead to conformational changes of Tec and translocation to the cytoplasmic membrane where, in a second step, Src kinases phosphorylate a conserved tyrosine residue in the catalytic domain thereby increasing Tec kinase activity. Autophosphorylation of a tyrosine residue in the SH3 domain further prevents the inhibitory intramolecular interaction resulting in a robust Tec kinase activation. 

New developments in immobilization surfaces have lead to the use of SPR biosensors to monitor protein interactions with lipid surfaces and membrane-associated proteins. Commercially available (BIACORE) hydrophobic and lipophilic sensor surfaces have been designed to create stable membrane surfaces. It has been shown that the hydrophobic sensor surface can be used to form a lipid monolayer (Evans and MacKenzie, 1999). This monolayer surface can be used to monitor protein-lipid interactions. For example, a biosensor was used to examine binding of Src homology 2 domain to phosphoinositides within phospholipid bilayers (Surdo et al., 1999). In addition, a lipophilic sensor surface can be used to capture liposomes and form a lipid bilayer resembling a biological membrane. 

Corvera, S. and Czech, M. R, Direct targets of phosphoinositide 3-kinase products in membrane traffic and signal transduction [review], Trends Cell. Biol., 8, 442-6, 1998. 

Ananthanarayanan, B., Ni, Q. and Zhang, J. (2005). Signal propagation from membrane messengers to nuclear effectors revealed by reporters of phosphoinositide dynamics and Akt activity. Proc. Natl. Acad. Sci. USA 102, 15081-6. 

The organization of lipids around the plasma membrane Ca2+-transport ATPase of erythrocytes has been also determined by FRET. Taking advantage of the intrinsic fluorescence of the ATPase due to tryptophan residues and labeling different types of lipids with pyrene, it was demonstrated that the transporter is preferentially surrounded by negatively charged lipids such as phosphoinositides [167],... 

Verbist, J., Gadella, T. W. J., Raeymaekers, L., Wuytack, F., Wirtz, K. W. A. and Casteels, R. (1991). Phosphoinositide-protein Interactions of the plasma-membrane Ca2+-transport ATPase as revealed by fluorescence energy-transfer. Biochim. Biophys. Acta 1063, 1-6. 

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... 

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