Basolateral cell membrane transporters

The successful application of in vitro models of intestinal drug absorption depends on the ability of the in vitro model to mimic the relevant characteristics of the in vivo biological barrier. Most compounds are absorbed by passive transcellular diffusion. To undergo tran-scellular transport a molecule must cross the lipid bilayer of the apical and basolateral cell membranes. In recent years, there has been a widespread acceptance of a technique, artificial membrane permeation assay (PAMPA), to estimate intestinal permeability.117118 The principle of the PAMPA is that, diffusion across a lipid layer, mimics transepithelial permeation. Experiments are conducted by applying a drug solution on top of a lipid layer covering a filter that separates top (donor) and bottom (receiver) chambers. The rate of drug appearance in the bottom wells should reflect the diffusion across the lipid layer, and by extrapolation, across the epithelial cell layer. 

Figure 9.7 Intestinal peptide transport. Peptides are taken upinto enterocytes together with H+ ions. The proton gradient is maintained via an Na + /H+ antiport system in the apical cell membrane. The Na+ gradient is guaranteed by the Na + /I<+-ATPase in the basolateral cell membrane.

Cephaloridine-induced nephrotoxicity is not restricted to the S2 segment but also involves the S3 segment of the proximal tubule [86]. More recent studies suggest that the rat renal organic anion transporter 1 (OATl) located in the renal basolateral cell membrane. 

The tight junction is a component of the junctional complexes which join cells. Immediately basolateral to the tight junction is the zonula adherens (Figs. 6 and 7). Because the zonula adherens and the gap junctions are focal contact regions, they do not impact transport by the paracellular pathway. All of these junctions are specialized regions of the lateral cell membrane which demarcate the lateral space. In certain types of cells the lateral space is rather narrow and... 

These methods of solute transfer usually rely on a relatively low intracellular concentration of the solute of interest, so that it will readily diffuse into the cell down the electrochemical gradient (as in the case of ion channels). Alternatively, the solute may be moved into the cell using chemical energy derived from another solute moved in the same direction (co-transport) or opposite direction (countertransport) on the carrier protein (symporters and antiporters respectively). The transfer of the second solute is in turn dependent on an inward electrochemical gradient. Ultimately, these gradients are established by primary, energy-requiring solute pumps (e.g. ATPases), which, on most epithelia, are located on the basolateral/serosal membrane (see Section 5.2 for discussion of ATPases). 

The mechanism by which Na" is reabsorbed in coupled exchange with and K+ in the collecting duct has been discussed previously that is, Na+-driven K+ secretion is partially under mineralocorticoid control. Aldosterone and other compounds with mineralocorticoid activity bind to a specific mineralocorticoid receptor in the cytoplasm of late distal tubule cells and of principal cells of the collecting ducts. This hormone-receptor complex is transported to the cell nucleus, where it induces synthesis of multiple proteins that are collectively called aldosterone-induced proteins. The precise mechanisms by which these proteins enhance Na+ transport are incompletely understood. However, the net effect is to increase Na" entry across apical cell membranes and to increase basolateral membrane Na+-K+-ATPase activity and synthesis. 

Figure 12.6 Mechanism of action of mineralocortjcoid receptor antagonists in the collecting tubule. Aldosterone enters the tubular cell by the basolateral surface and binds to a specific mineralocorticoid receptor (MNR) in the cytoplasm. The hormone receptor complex triggers the production of an aldosterone-induced protein (AlP) by the cell nucleus (NUC). The AIP acts on the sodium ion channel (ic) to augment the transport of Na+across the basolateral membrane and in to the cell. An increase in AIP activity leads to the recruitment of dormant sodium ion channels and Na pumps (P) in the cell membrane. AIP also leads to the synthesis of new channels and pumps within the cell. The increase in Na+conductance causes electrical changes in the luminal membrane that favour the excretion of intracellular cations, such as K+and H-h. Spironolactone competes with aldosterone for the binding site on the MNR and forms a complex which does not excite the production of AIP by the nucleus.

Lowes, S., and N.L. Simmons. 2001. Human intestinal cell monolayers are preferentially sensitive to disruption of barrier function from basolateral exposure to cholic acid Correlation with membrane transport and transepithelial secretion. Pflugers Arch 443 265. 

Apart from causing very well known cardiotoxic effects, phenothiazine derivatives can accumulate in lung epithelial cell membranes and therefore cause severe respiratory disorders. In the study performed by Ito et al. [279] it was found that CPZ (9) inhibited transepithelial Cl transport, mainly due to two mechanisms influence on the beta-adrenergic receptor and inhibition of basolateral potassium channels. The authors of this study also suggested that the recorded effects could result from the electrostatic interactions between the drug molecules and negatively charged components of the inner leaflet of the plasma membrane. 

The resultant decrease in pH value leads to an increase in binding affinity to the protective Fc-Rn, and to degradation by proteases of unbound antibody molecules. The degradation products will reside in the lysosome, while the intact IgG molecules bound to Fc-Rn will be transported to the cell membrane and can be returned intact to the extracellular space. The Fc-Rn can transport the bound antibody bidirectionally to the apical and basolateral membrane, delivering it to the interstitial fluid or the systemic circulation. As a result, the residence time of the intact antibody in the body is prolonged. 

In addition to factors Influencing luminal uptake of zinc, transfer across the basolateral membrane has been shown to be dependent on the concentration of albumin in the portal circulation (33). These investigations suggest that metabolic factors which affect the albumin concentration in the plasma may also affect the rate of portal zinc transfer. It should be noted that EDTA did not enhance zinc accumulation within the mucosal cells yet it Increased transfer to the vascular perfusate. These results suggest that basolateral membrane transport of zinc is enhanced by EDTA. We have proposed (35), as has Davies (38), that basolateral transport to the circulation is the rate limiting phase of zinc absorption. Since EDTA and zinc might be transported as a complex (42), the latter may transverse this barrier more easily and thus Increase zinc absorption. 

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