Membrane penetration

It has been proposed " that the mechanism(s) of action of gymnemic acids and ziziphins is a biphasic, model-membrane penetration-process. The model suggested that the modifier molecules interact first with the receptor-cell plasma-membrane surface. It was postulated that this initial interaction involves a selective effect on taste perception, including the transduction and quality specification of the sweet stimuli, and selective depression of sweetness perception. Following the initial interaction, the modifier molecules interact with the membrane-lipid interior to produce a general disruption of membrane function and a nonselective effect on taste... 

Octanol-water partition (log P) and distribution (log D) coefficients are widely used to make estimates for membrane penetration and permeability, including gastrointestinal absorption [77, 78], BBB crossing [60, 69] and correlations to pharmacokinetic properties [1]. The two major components of lipophilicity are molecular size and H-bonding [57], which each have been discussed above (see Sections 2.5 and 2.6). 

As chronicled by Dearden [21], the association of compound lipophilicity with membrane penetration was first implied by Overton and Meyer more than a century ago. To enhance this understanding, lipophilicity measurements were initially performed using a variety of lipid phases [22], while the comprehensive review by Hansch et al. [23], with extensive data from literature and their own measurements, lent further support to the now accepted wide use of the octanol-water solvent system. 

Bai, J., Tucker, W. C. and Chapman, E. R. PIP2 increases the speed of response of synaptotagmin and steers its membrane-penetration activity toward the plasma membrane. Nat. Struct. Mol. Biol. 11 36-44,2004. 

It has been assumed implicitly in the preceding analyses that penetration of the substrate into the film and its exiting are fast, so that equilibrium is maintained and characterized by a partition coefficient. If this assumption is not valid, the rate of penetration (rate constant kfp) interferes with the current response, giving rise to an additional characteristic current, ifp = FSkfpCwhere kfp either represents a membrane penetration or... 

Curtain, C.C., Ali, F., Volitakis, I., Cherny, R.A., et al. (2001) Alzheimer s disease amyloid-beta binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits, J. Biol. Chem., 276, 20466-20473. 

A. Chattopadhyay and E. London, Parallax method for direct measurement of membrane penetration depth utilizing fluorescence quenching by spin-labeled phospholipids, Biochemistry 26, 39-45 (1987). 

Finally, membrane penetration may occur in the form of small membrane-covered vesicles. Two different systems are considered. 

The pharmacokinetics of cardiac glycosides (A) are dictated by their polarity, i.e the number of hydroxyl groups. Membrane penetrability is virtually nil in ouabain, high in digoxin, and very high in digitoxin. Ouabain (g-strophanthin) does not penetrate into cells, be they intestinal epithelium, renal tubular, or hepatic cells. At best, it is suitable for acute intravenous induction of glycoside therapy. 

The numerous negative charges are significant in several respects (1) they contribute to the poor membrane penetrability—heparin is ineffective when applied by the oral route or topically onto the skin and must be injected (2) attraction to positively charged lysine residues is involved in complex formation with ATIII (3) they permit binding of heparin to its antidote, protamine (polycationic protein from salmon sperm). 

Diminished cellulat uptake may result from reduced synthesis of a transport protein that may be needed for membrane penetration (e.g., methotrexate). 

Cyclic peptides are important biologically active compounds that combine peptide properties with conformational bias and often improved serum stability and membrane penetration [1-3]. Depsipeptides are similar compounds, but they contain as part of their backbone one or more hydroxylated amino acid residues that add ester or lactone moieties to the peptide (Fig. 1) [4-6]. Cyclo- and... 

Figure 12.5 Patterns generated upon addition of a membrane surface-binding molecule (I), membrane penetrating compound (II), and a compound that does not interact with membranes (III). Adapted from Katz et al. (2006). Copyright 2006 Springer. (See color insert.)...

Evrard D, Touitou E, Kolusheva S, Fishov Y, Jelinek R. A new colorimetric assay for studying and rapid screening of membrane penetration enhancers. Pharm Res 2001 18 943-949. 

Katz M, Tsubery H, Kolusheva S, Shames A, Fridkin M, Jelinek R. Lipid binding and membrane penetration of polymyxin B derivatives studied in a biomimetic vesicle system. Biochem J 2003 375 405-413. 

SENSORY MECHANISM ionic differences at membrane pH, anion effects on membrane membrane penetration ion channel protein binding specific protein binding ion channel protein binding protein complexation generalized membrane interaction... 

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