Interactions with membrane proteins

FIGURE 5.3 Different types of functional readouts of agonism. Receptors need not mediate cellular response but may demonstrate behaviors such as internalization into the cytoplasm of the cell (mechanism 1). Receptors can also interact with membrane proteins such as G-proteins (mechanism 2) and produce cytosolic messenger molecules (mechanism 3), which can go on to mediate gene expression (mechanism 4). Receptors can also mediate changes in cellular metabolism (mechanism 5). 

Flavonoids can also interact with membrane proteins, such as those functioning as receptors, transporters, channels, and enzymes, and potentially affect their biological activities. A summary of recent advances on the study of flavonoid interactions with plasma membrane proteins is presented in Table 4.2. 

NaCIO is an acknowledged novel absorption enhancer for ampicillin sodium [99], glycyr-rhizin [100,101], gentamicin [102], phenoxymethyl penicillin [103], cefoxitin sodium [104,105], and acyclovir [106], Takahashi et al. [107] reported that the enhanced membrane permeability of phenolsulfonphthalein depends on the disappearance kinetics of CIO from the loop and its calcium ion sequestration capacity. The enhancing mechanisms of NaCIO are proposed to be involved in (1) Ca2+ sequestration, (2) increase in pore size and solvent drag, (3) interaction with membrane proteins and lipids, and (4) increase in the intracellular calcium level [104,105,108-111],... 

The final chapter, The Role of the Membrane Actions of Phenothiazines and Flavonoids as Functional Modulators by K. Michalak, O. Wesolowska, N. Motohashi and A. B. Hendrich, presents a very comprehensive review on important biological effects of phenothiazines and flavonoids due to interactions with membrane proteins and the lipid phase of membranes. The discussion includes the influence of these heterocycles on model and natural membranes, modulation of MDR transporters by these heterocycles, and the effects of these hetero cycles on ion channel properties. This review may attract much interest from medicinal and pharmaceutical chemists as well as heterocyclic chemists in the life science fields. 

However, this system has several limitations (1) It enables the detection of binary interactions but not global characterization of multiprotein networks (2) it is not optimal to detect protein-protein interactions that depend on post-translational modifications and interactions with membrane proteins (3) it can generate many false positives or false negatives. 

The mechanism of action of general anaesthetics is unknown, but there are two theories to explain their action the lipid theory and the protein theory. The lipid theory states that general anaesthetics interact with lipids in the neuronal cell membrane and disrupt neurotransmission and the protein theory states that general anaesthetics interact with membrane proteins to alter release of neurotransmitters. The protein theory is thought most likely. 

The ability of lipid molecules to associate in an aqueous environment into infinite lipid bilayers is the basic mechanism behind the formation of biomembranes and the ability to separate compartments of functional units by such membranes was an important step in the development of organized life. The significance of the ordered but fluid state of lipid molecules, particularly for the interaction with membrane proteins, was revealed by studies of lipid-water systems during the 1960s (see Chapman etal., 1967). This knowledge was summarized (Singer and Nicolson, 1972) in the well-known fluid-mosaic model of the cell membrane. 

Fig. 6.2 Interactions between phospholipids, membrane proteins, and flavonoids. (a) In acidic and neutral conditions, flavonoids such as quercetin intercalate between phospholipids in the hydrophobic zone and initiate the formation of an ordered lipid phase. Flavonoids can also interact with membrane proteins, (b) In alkaline conditions, deprotonated flavonoids cover the polar head surface of phospholipids and interact with membrane proteins, (c) When phloretin replaces quercetin, the distance between the hydrocarbon chains is increased and lipids form a superordered lipid phase. Intercalation of phloretin between the polar heads of phospholipids induces micelle formation, (d) Outer and inner phospholipidic layers can be interdigitated when phospholipids are spaced by phloretin but not by quercetin (a and b). Modified from Tarahovsky et al. (2008).

Changes of lipid levels and compositions could alter the matrix in interactions with membrane proteins (e.g., ion channels), thereby influencing the protein configurations and functions. Moreover, alterations in membrane lipid components could also affect the microenvironments in cellular communication and cytosolic ion distribution. In this regard, glycolipids and gangliosides play important roles in the former while anionic lipids are the main players in the latter. 

Interact with membrane proteins affecting their correct function,... 

Fantini J, Barrantes FJ. How cholesterol interacts with membrane proteins an exploration of cholesterol-binding sites including CRAG, CARC, and tilted domains. Front Physiol. 2013 4 31. 

However, it is evident that the observed inhibitory effects are non-sequence dependent, and this may be tentatively explained by unspecific interactions with membrane proteins, thus interfering with CD4/Gpl20 interactions. 

Membrane and tight junction modulation Macrolides influence membrane properties, most likely via insertion and thereby function in both ion permeability and the interaction with membrane proteins. 27... 

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