Basolateral cell surface membrane receptors

In the bloodstream, ferric iron binds tightly to circulating plasma transferrin (TF) to form diferric transferrin (FeTF). Absorption of iron into erythrocytes depends on basolateral membrane receptor-mediated endocytosis of FeTF by transferrin receptor 1 (TfR 1). FeTF binds to TfR 1 on the surface of erythroid precursors. These complexes invaginate in pits on the cell surface to form endosomes. Proton pumps within the endosomes lower pH to promote the release of iron into the cytoplasm from transferrin. Once the cycle is completed,TF and TfR 1 are recycled back to the cell surface. TF and TfR 1 play similar roles in iron absorption at the basolateral membrane of crypt enterocytes (Parkilla et al., 2001 Pietrangelo, 2002). 

Another feature of tumor cells, particularly those with high malignancy, is the loss of cellular polarity. Normal, non-transformed cells, with the exception of blood cells, have a clearly polarized structure i) surface membrane structure involved in cell-to-cell or cell-to-extracellular matrix adhesion ii) surface structure open to the external environment and involved in endocytosis or exocytosis. Structure (i) in epithelial cells, termed basolateral surface, is rich in adhesion receptors including integrins (ii), termed apical surface, has much higher level of sphingolipids,... 

For example, widely used protein therapeutic insulin is not transported by paracellular diffusion. It is demonstrated that insulin is transported by a process of endocytosis [5]. Some other proteins have been shown to be transported by binding to cell surface receptors and binding proteins [6]. However, only a small fraction is released at basolateral membrane and secreted into interstitial spaces in active intact form. Some reports demonstrated that therapeutic concentrations of proteins and peptides can be achieved if these compounds can withstand proteolytic enzymes in the G1 tract [7]. 

Heparan sulfate proteoglycans and the coreceptors have been localized predominantly to the basolateral surface of WD HAE cells (47), which correlates with preferential transduction of these cells when vector is applied to the basolateral membrane relative to the apical membrane. However, binding studies of radiolabeled AAV-2 have shown only a four- to sevenfold reduction in binding to the cal membrane of WD HAE in culture as compared to the basal membrane. Because gene transfer efficiency was 200- fold greater following basal application than for luminal qiplication, the existence of apical membrane receptors for AAV-2 that are not functional for vector expression have been proposed (47,94). 

The taste cells are situated in the lingual epithelium with the apical membrane exposed to the mucosal surface of the oral cavity and the basal surface in contact with the nerve [interstitial fluid] [FIGURE 10]. Within the basolateral surface are the nerves which respond to the chemestiietic stimulants, i.e. direct nerve stimulation. The microvilli at the apical membrane contain receptor proteins which respond to sweeteners, some bitters and possibly coolants. The olfactory cells are bipolar neurons with dendritic ends containing cilia exposed to the surface and axons linked to the brain, where they synapse in the olfactory bulb. The transfer of information from this initial stimulus-receptor interaction to the brain processing centers involves chentical transduction steps in the membrane and within the receptor cells. The potential chemical interactions at the cell membrane and within the cell are schematically outlined in FIGURE 10. 

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.

Similar to the oq-ARs, our knowledge of the cellular trafficking properties of the oq-AR family is not as nearly refined as that for the P-ARs. Three oq-ARs (oqA, oqB, and oqc) have been isolated, cloned, and characterized. An overview of the nature of the oq-AR subtypes, their localization, and their cellular trafficking properties has been published (58). Reminiscent of the oq-ARs, subtypes of the oq-ARs are differentially localized within the cell. Indeed, results from studies conducted with polarized Madin-Darby canine kidney cells showed that the oq-ARs are selectively expressed on the basolateral surface (exposed to the blood) as opposed to the apical aspect (exposed to urine) of these renal cells (59,60). In investigating the mechanism forthis differential localization, Wozniak and Limbird (60) noted that oqA-AR is inserted directly and selectively into the basolateral membrane. The targeting of this receptor to the basolateral aspect is determined by a sequence as yet poorly defined near the lipid—oqA- AR interface ... 

Figure 8,1, Routes and mechanisms of solute transport across epithelial membranes. In general, routes 2-5 are transcellular pathways (i.e., compounds move through the cells), whereas route 1 is considered a paracellular pathway (i.e., a compound moves between the cells). (l)Tight junctional pathway (2) drug efflux pathway (e.g., P-glycoprotein mediated) (3) passive diffiision (4)receptor-mediated endocytosis and/or transc3dosis pathways (5) carrier-mediated route. Note that receptor and carrier proteins in epithelial cells are expressed on both the apical and basolateral surfaces.

Vitamin B,. Vitamin Bi2 the colloquial name for cobalamin (Cbl), is a large polar molecule that must be bound to specialized transport proteins to gain entry into cells. After oral administration it is bound to intrinsic factor (IF), a protein released from the parietal cells in the stomach and proximal cells in the duodenum. The Cbl-IF complex binds to an IF-receptor located on the surface of the ileum, which triggers a yet undefined endocy-totic process. After internalization, the fate of the IF-Cbl complex has yet to be clarified. It vvas reported that IF-Cbl complex dissociates at acidic pH, and Cbl is transferred to transco-balamin II by Ramasamy and coworkers (94), whereas Dan and Cutler (95) found evidence of free Cbl in endosomes and the basolateral side of the membrane after administration to the apical surface of Caco-2 cell monolayers. It is clear, however, that Cbl is transported into all other cells only when bound to transcobal-amin II. 

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