Membrane transport proteins acid transporter

The removal of released DA from the synaptic extracellular space to facilitate its intraneuronal metabolism is achieved by a membrane transporter that controls the synaptic concentration. This transporter has been shown to be a 619 amino-acid protein with 12 hydrophobic membrane spanning domains (see Giros and Caron 1993). Although it has similar amino-acid sequences to that of the NA (and GABA) transporter, there are sufficient differences for it to show some specificity. Thus DA terminals will not concentrate NA and the DA transporter is blocked by a drug such as nomifensine which has less effect on NA uptake. Despite this selectivity some compounds, e.g. amphetamine and 6-OHDA (but not MPTP), can be taken up by both neurons. The role of blocking DA uptake in the central actions of cocaine and amphetamine is considered later (Chapter 23). 

From a genetical point of view, Saccharomyces cerevisiae is an ideal organism which may be considered the Escherichia coli of eukaryotic cells [4,5]. This is true in particular for the study of metabolic regulation and for that of membrane transport [6]. Finally, the astonishing resemblance between many yeast proteins and certain mammalian-cell proteins has seriously broadened the scope of interest. Although a few reports have appeared on amino acid transport in some other yeasts, most investigations in this field have used strains of Saccharomyces cerevisiae. 

W. N. Fischer. B. Andre, D. Rentsch, S. Krolkiewicz, M. Tegeder, K. Breitkreuz, and W. B. Frommer, Amino acid transport in plants. Trends Plant Sci. 3 188 (1998), H. Y. Steiner, W. Song, L. Zhang, F. Naider, J. M. Becker, and G. Stacey, An Arahidopsis peptide transporter is a member of a novel family of membrane transport proteins. Plant Cell 6 189 (1994). 

Dutta-Roy, A.K. (2000) Cellular uptake of long chain fatty acids role of membrane associated fatty acid binding/transport proteins. Cellular and Molecular Life Sciences (in press). 

Adrenoleukodystrophy is an X-linked dysmyelinative disorder caused by mutations in the ABCD1 gene, which encodes the peroxisomal integral membrane ALD protein, a member of the ATP binding cassette transporter family. These mutations result in impaired clearance of plasma very-long-chain fatty acids. Affected males may present with symmetrical distal axonal polyneuropathy, adrenocortical insufficiency or CNS demyelination, while occasional heterozygous women demonstrate deficits suggestive of multiple sclerosis [56]. Manipulation of dietary fatty acid intake has some minimal therapeutic effect, while bone marrow transplantation has diminished deficits in a few patients. (See in Ch. 41.)... 

All botulin neurotoxins act in a similar way. They only differ in the amino-acid sequence of some protein parts (Prabakaran et al., 2001). Botulism symptoms are provoked both by oral ingestion and parenteral injection. Botulin toxin is not inactivated by enzymes present in the gastrointestinal tracts. Foodborne BoNT penetrates the intestinal barrier, presumably due to transcytosis. It is then transported to neuromuscular junctions within the bloodstream and blocks the secretion of the neurotransmitter acetylcholine. This results in muscle limpness and palsy caused by selective hydrolysis of soluble A-ethylmalemide-sensitive factor activating (SNARE) proteins which participate in fusion of synaptic vesicles with presynaptic plasma membrane. SNARE proteins include vesicle-associated membrane protein (VAMP), synaptobrevin, syntaxin, and synaptosomal associated protein of 25 kDa (SNAP-25). Their degradation is responsible for neuromuscular palsy due to blocks in acetylcholine transmission from synaptic terminals. In humans, palsy caused by BoNT/A lasts four to six months. 

Gruber HJ, Low PS Interaction of amphiphiles with integral membrane proteins. I. Structural destabilization of the anion transport protein of the erythrocyte membrane by fatty acids, fatty alcohols and fatty amines. Biochim Biophys Acta 1988 944 414-424. 

All clinical forms of the disease are due to a defect in the lysosomal membrane transporter for sialic acid necessary for the export of sialic acid out of the lysosome [11]. The gene coding for this transporter, SLC17A5, contains 11 exons and encodes a 495-amino-acid transmembrane protein, sialin [20]. 

As hormone-sensitive lipase hydrolyzes triacylglyc-erol in adipocytes, the fatty acids thus released (free fatty acids, FFA) pass from the adipocyte into the blood, where they bind to the blood protein serum albumin. This protein (Mv 66,000), which makes up about half of the total serum protein, noncovalently binds as many as 10 fatty acids per protein monomer. Bound to this soluble protein, the otherwise insoluble fatty acids are carried to tissues such as skeletal muscle, heart, and renal cortex. In these target tissues, fatty acids dissociate from albumin and are moved by plasma membrane transporters into cells to serve as fuel. 

Whereas a major function of biological membranes is to maintain the status quo by preventing loss of vital materials and entry of harmful substances, membranes must also engage in selective transport processes. Living cells depend on an influx of phosphate and other ions, and of nutrients such as carbohydrates and amino acids. They extrude certain ions, such as Na+, and rid themselves of metabolic end products. How do these ionic or polar species traverse the phospholipid bilayer of the plasma membrane How do pyruvate, malate, the tricarboxylic acid citrate and even ATP move between the cytosol and the mitochondrial matrix (see figs. 13.15 and 14.1) The answer is that biological membranes contain proteins that act as specific transporters, or permeases. These proteins behave much like conventional enzymes They bind substrates and they release products. Their primary function, however, is not to catalyze chemical reactions but to move materials from one side of a membrane to the other. In this section we discuss the general features of membrane transport and examine the structures and activities of several transport proteins. 

The transport or release of iron has been much discussed. One view is that the iron is transferred from the siderophore complex at the outer membrane to another membrane-bound protein, for example in the uptake of iron by rhodotorulic acid in Rhodotorula. The other view is that the intact Fein-siderophore complex is taken up into the cell. This is supported by studies with inert chromium(III) complexes in E. coli and also by labelling studies. 

Carrier-mediated membrane transport proteins on the RPE selectively transport nutrients, metabolites, and xenobiotics between the choriocapillaris and the cells of the distal retina, and include amino acid [33 35], peptide [36], dicarboxylate, glucose [37], monocarboxylic acid [38,39], nucleoside[40], and organic anion and organic cation [41] transporters. Membrane barriers such as the efflux pumps, including multidrug resistance protein (P-gp), and multidrug resistance-associated protein (MRP) pumps have also been identified on the RPE. Exploitation of these transport systems may be the key to circumventing the outer BRB. 

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