Brain receptor mediated uptake systems

TfR-mediated endocytosis is a well-known uptake system Tf binds one or two Fe atoms, but only diferric Tf (Fe2Tf) has a high affinity for TfR to be taken up by the receptor-mediated endocytosis. This system uses a mobilization pathway that involves endosomal acidification, reduction of ferric Fe, and ferrous Fe transport [8]. Recently, it was clarified that divalent cation/ metal ion transporter (DCT1) or Nramp2 involves iron transport from the endosome to the cytosol [9, 10]. Al resembles Fe in chemical characteristics ionic radius, charge density, and coordination number [11]. Therefore, Al binds with Tf to form di—Al—Tf. Al bound to Tf even passes through the blood-brain barrier to enter the neuronal cells via Tf receptor-mediated endocytosis [12]. 

Specific nutrient transport systems in brain capillaries can be used to facilitate drug entry into the brain. L-dopa (L-3,4-dfiiydroxyphenylalanine), a metabolic precursor of dopamine, is transported across endothelial cells by the neutral amino acid transport system [5], r-dopa permeates through capillaries into the striatal tissue, where it is decarboxylated to form dopamine. Therefore, systemic administration of L-dopa is often beneficial to patients with Parkinson s disease. Certain protein modifications, such as cationization [6] and anionization [7], produce enhanced uptake in the brain. Modification of drugs [8,9] by linkage to an antitransferrin receptor antibody also appears to enhance transport into the brain. This approach depends on receptor-mediated transcytosis of transferrin-receptor complexes by brain endothehal cells substantial uptake also occurs in the Hver. 

Fig. 3. Model of the life cycle of prions. PrP is synthesized in the rough endoplas-matic reticulum (ER), and after passing through the secretory pathway including the Golgi and secretory vesicles, reaches the surface of a PrP infectable cell where it is anchored via a glycosylphosphatidyl inositol (GPI) moiety. Endocytosis of PrP and possibly PrP via clathrin coated vesicles could be mediated by the 37 kDa laminin receptor precursor (LRP). The uptake of the infectious agent could also be LRP independent. The conversion of the internalized PrP to PrP is thought to take place in the endo-somes, lysosomes, or endolysosomes. Molecular chaperones could be involved in this conversion process. PrP replication and aggregation can occur in neuronal cells of the brain but also in the cells constituting the lymphoreticular system. Alternatively, endocytosis and conversion of PrP into PrP could happen in caveolae-like domains (CLDs).

Anandamide (AEA) is the most studied member of a new class of lipid mediators, collectively called endocannabinoids. The biological activity of AEA at cannabinoid and noncannabinoid receptors depends on its Hfe span in the extracellular space, which is regulated by a rapid cellular uptake, followed by intracellular degradation by the enzyme AEA hydrolase (fatty acid amide hydrolase). Here, we present the methodological details of the procedures that we have developed to assay fatty acid amide hydrolase activity and to characterize AEA transport through cell membranes in a new ideal ex vivo system like brain synaptosomes. 

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