Permeation pathway

Neurotransmitter transport can be electrogenic if it results in the net translocation of electrical charge (e.g. if more cations than anions are transferred into the cell interior). Moreover, some transporters may direction-ally conduct ions in a manner akin to ligand-gated ion channels this ion flux is not coupled to substrate transport and requires a separate permeation pathway associated with the transporter molecule. In the case of the monoamine transporters (DAT, NET, SERT) the sodium current triggered by amphetamine, a monoamine and psychostimulant (see Fig. 4) is considered responsible for a high internal sodium concentration... 

Molecular biology studies have identified a loop containing 20-25 amino acid residues between S5 and S6 (or Ml and M2, Fig. 2) forming the pore. The G(Y/F) G motif located in the pore represents the K+-selectivity signature, which is common to all K+ channels. The external entry to the channel pore and its adjacent residues constitute binding sites for toxins and blockers. The internal vestibule of the pore and the adjacent residues in S5 and S6 contribute to binding sites for compounds such as 4-aminopyiidine and quinidine. The S4-S5 linker lies close to the permeation pathway and is required for... 

The permeation pathways of all ionotropic glutamate receptors are similar, but vice la difference 280... 

The relationship between the different conductances of the glutamate transporter is not well-understood. The structural basis for these conductances and whether the anions and glutamate permeate the same pore of the transporter protein is not known. Sonders and Amara (40) proposed two models a single pathway for substrate and the uncoupled anion movement (Fig. 3A), or multiple permeation pathways in a single transporter molecule (Fig. 3B) (40). This idea will be discussed further in relation to what is known about the quaternary structure of glutamate transporters. 

Originating from the structure of the stratum corneum, two permeation pathways are possible (a) the intercellular route and (b) the transcellular route. 

Frequently, histopathological examinations of tissues reveal invaluable information on their toxicities [11], The ability to screen various formulations quickly for both ciliotoxicity and other forms of epithelial toxicities is a strong positive attribute of the ex vivo models. Furthermore, advanced techniques such as confocal laser scanning microscopy can be used to study the drug permeation pathways of these tissues [12],... 

Figure 20.2 A skin model showing possible diffusion pathways and its equivalent circuit diagram, (a) Permeation pathways in a two-dimensional skin model, (b) Resistances in a two-dimensional skin model.

For parallel permeation pathways within a single layer of such a laminate, the total permeability may be calculated as the sum of the permeabilities [49], For example, when assuming that permeation may occur through both a lipid fraction and a protein fraction of the stratum corneum, the total permeability is calculated according to Eq. 34 ... 

Mitragotri S (2003) Modeling skin permeability to hydrophilic and hydrophobic solutes based on four permeation pathways. J Contr Rel 86 69-92. 

Figure 6.1 Schematic representation of the intestinal membrane structure. The singlet arrow in the figure illustrate the permeation pathways, (a) Villous structure of intestine. Unstirred water layer is adjacentto villi, (b) Permeation pathways of compounds across the intestinal epithelial membrane. (Adapted from [14] and modified from Bentham Science Publishers, Ltd.)...

The paracellular permeation pathway in the intestinal cell monolayer models is often limited. Therefore these models are not suitable for predicting permeability of paracellularly absorbed compounds. The average pore radius in Caco-2 cells (<6 A) is more representative of the colon than the small intestine (8-13 A)and paracellular transport can be up to 100-fold lower in Caco-2 cells than in the small intestine. Investigation of a rat intestinal cell line 2/4/Al, which forms polarized cell mono-layers and has an average pore radius (9 A) more representative of the small intestine, showed improved prediction of oral absorption for incompletely absorbed drugs [24, 25]. 

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