Cell membranes and transport

Like the glucose carrier, the carriers for large neutral amino acids, the so-called L-system - now designated LAT - are present at both sides of the endothelial cell membranes and transport at least 10 essential amino acids. The L-transporter at the BBB has a much higher transport capacity than those in other tissues. Its marked preference for phenylalanine analogs explains why the anticancer drugs melphalan and d,l-NAM-7 are transported by the L-system, as is the L-Dopa used to treat Parkinson s disease [42]. 

The IF-cobalamin complex binds to specific receptors on the luminal surface of ileal mucosal cells. Binding requires Ca + and occurs optimally at pH >6.6. IF may enter the mucosal cell with cobalamin, or it may bind to the receptor and release the vitamin into the cell interior. The IF-receptor complex may then remain on the cell membrane and transport other molecules of cobalamin into the cell. 

Simple diffusion has been suggested to be the important mechanism for transporting small molecules through the cell membrane, and transport of large molecules is most likely mediated by transport vesicles loaded with biopolymers budding off from donor membranes and fusion to acceptor membranes before delivering the load to the external medium. 

Total internal reflection fluorescence (TIRF) microscopes are employed to study a diverse phenomena, including cell transport, signaUng, replication, motility, adhesion, and migration cell membranes and transport the structure of ribonucleic acid (RNA) neurotransmitters and virology. 

PAF is a hydrophobic molecule and for crossing cell membranes and transportation to its various sites of action, serum albumin serves a carrier function. When injected into mammals, PAF produces both the signs and symptoms of anaphylaxis with hypotension, increased vascular permeability and hemoconcentration, thrombo-... 

One reason for this may be that the enzyme caimot be secreted, ie, transported across the cell membrane and cell wall of the host into the medium. 

Fig. 3-4 Electron transport process schematic, showing coupled series of oxidation-reduction reactions that terminate with the reduction of molecular oxygen to water. The three molecules of ATP shown are generated by an enzyme called ATPase which is located in the cell membrane and forms ATP from a proton gradient created across the membrane.

Alternatively, one interesting drug delivery technique exploits the active transport of certain naturally-occurring and relatively small biomacromolecules across the cellular membrane. For instance, the nuclear transcription activator protein (Tat) from HIV type 1 (HlV-1) is a 101-amino acid protein that must interact with a 59-base RNA stem-loop structure, called the traus-activation region (Tar) at the 5 end of all nascent HlV-1 mRNA molecules, in order for the vims to replicate. HIV-Tat is actively transported across the cell membrane, and localizes to the nucleus [28]. It has been found that the arginine-rich Tar-binding region of the Tat protein, residues 49-57 (Tat+9 57), is primarily responsible for this translocation activity [29]. 

In many epithelia Cl is transported transcellularly. Cl is taken up by secondary or tertiary active processes such as Na 2Cl K -cotransport, Na Cl -cotransport, HCOJ-Cl -exchange and other systems across one cell membrane and leaves the epithelial cell across the other membrane via Cl -channels. The driving force for Cl -exit is provided by the Cl -uptake mechanism. The Cl -activity, unlike that in excitable cells, is clearly above the Nernst potential [15,16], and the driving force for Cl -exit amounts to some 2(f-40mV. 

Figure 1 General pathways through which molecules can actively or passively cross a monolayer of cells. (A) Endocytosis of solutes and fusion of the membrane vesicle with the opposite plasma membrane in an active process called transcytosis. (B) Similar to A, but the solute associates with the membrane via specific (e.g., receptor) or nonspecific (e.g., charge) interactions. (C) Passive diffusion between the cells through the paracellular space. (C, C") Passive diffusion (C ) through the cell membranes and cytoplasm or (C") via partitioning into and lateral diffusion within the cell membrane. (D) Active or carrier-mediated transport of an otherwise poorly membrane permeable solute into and/or out of a cellular barrier.

The permeability of the cell monolayer consists of parallel transcellular and paracellular pathways. In passive diffusional transport, it is generally taken that uncharged molecules are capable of partitioning into the cell membrane and... 

The mechanism of the slow-wave potential is unclear. One hypothesis is that the rate at which sodium ions are actively transported out of the cell rhythmically increases and decreases. A decrease in the outward movement of Na+ ions allows positive charges to accumulate along the internal surface of the cell membrane and depolarization takes place. This is followed by an increase in the outward movement of Na+ ions, which causes the internal surface of the cell membrane to become more negative, and repolarization takes place. 

There are two pathways by which a drug molecule can cross the epithelial cell the transcellular pathway, which requires the drug to permeate the cell membranes, and the paracellular pathway, in which diffusion occurs through water-filled pores of the tight junctions between the cells. Both the passive and the active transport processes may contribute to the permeability of drugs via the transcellular pathway. These transport pathways are distinctly different, and the molecular properties that influence drug transport by these routes are also different (Fig. 

Let us conclude this section by proposing that provided that the drug is sufficiently soluble in the gastrointestinal fluids, the complex process of intestinal drug absorption can often be satisfactorily described by focusing on passive transport across the cell membrane, and that the development of models that predict passive transcellular permeability is particularly important. Such models are the focus of the remaining part of this chapter. 

P-gp substrates are in general either neutral or cationic at physiological pH (weak bases). Weak bases can cross the lipid membrane in the uncharged form and reprotonate in the negatively charged cytosolic leaflet of the membrane. With a few exceptions (e.g., the tetraphenyl phosphonium ion, which can reach the cytosolic membrane leaflet due to charge delocalization [70]), permanently charged cations do not cross the cell membrane and therefore cannot interact with P-gp in intact cells. They can, however, insert into the cytosolic leaflet in inside-out cellular vesicles and are then transported by P-gp [42, 71]. 

The specificity of several of the enzymes identified in the 4S pathway of different organisms has been studied. In case of the DBT desulfurizing enzymes, little difference is expected in the specificity of the enzymes, say DszA, from different Rhodococcus strains found to date. This is essentially because the DNA sequence for the enzymes investigated so far has been the same. The difference in the specificity observed with whole cell assays is essentially due to the differences in substrate intake via the cell membrane and not necessarily due to a difference in the intrinsic enzyme specificity. It has been found that while isolated enzyme DszC (from KA2-5-1) can desulfurize up to 4,6 dipropyl DBT, whole cells cannot, indicating substrate transport as limiting factor. 

Although the absence of paracellular transport across the BBB impedes the entry of small hydrophilic compounds into the brain, low-molecular-weight lipophilic substances may pass through the endothelial cell membranes and cytosol by passive diffusion [7]. While this physical barrier cannot protect the brain against chemicals, the metabolic barrier formed by the enzymes from the endothelial cell cytosol may transform these chemicals. Compounds transported through the BBB by carrier-mediated systems may also be metabolized. Thus, l-DOPA is transported through the BBB and then decarboxylated to dopamine by the aromatic amino acid decarboxylase [7]. 

The ideas of Overton are reflected in the classical solubility-diffusion model for transmembrane transport. In this model [125,126], the cell membrane and other membranes within the cell are considered as homogeneous phases with sharp boundaries. Transport phenomena are described by Fick s first law of diffusion, or, in the case of ion transport and a finite membrane potential, by the Nernst-Planck equation (see Chapter 3 of this volume). The driving force of the flux is the gradient of the (electro)chemical potential across the membrane. In the absence of electric fields, the chemical potential gradient is reduced to a concentration gradient. Since the membrane is assumed to be homogeneous, the... 

Abstract The supramolecular composites containing fullerenes C60 immobilized at nanosilica were used for the design of the molecular systems that can be an effective agent in cancer photodynamic therapy (PDT). In particular, it was shown that photoexcited fullerene C60-containing composites decrease viability of transformed cells, intensify the process of lipid peroxidation (LPO) in cell membranes and accumulation of low-molecular weight DNA fragments, and also decrease the activity of electron-transport chain of mitochondria. 

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