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PubMed1997

Membrane associated fatty acid binding protein (FABPpm) in human skeletal muscle is increased by endurance training.

Endurance training increases the capacity for utilization of fatty acids. Since fatty acids are believed to enter cells via facilitated diffusion a possible mechanism behind this adaptation to training might be a training-induced increase in membrane content of putative fatty acid transporters. We investigated whether the expression of the 40 KD membrane associated fatty acid binding protein (FABPpm) in skeletal muscle is increased with endurance training in man. The FABPpm was detectable in a crude membrane preparation from human skeletal muscle. Three weeks of intense one-legged endurance training increased (p < 0.05) the content of FABPpm by 49% whereas in the untrained control muscle no change was observed. In addition, the activity of citrate synthase was increased (p < 0.05) by 20% in the trained compared with the untrained muscle. It is concluded that expression of FABPpm in human skeletal muscle is increased with endurance training consistent with a role of FABPpm as a sarcolemmal fatty acid transporter.

Adult↗
PubMed1997

Transport of alpha-ketoisocaproate in neuroblastoma NB-2a cells.

Transport of alpha-ketoisocaproate (KIC), a ketoacid originating from leucine and proposed to be involved in the buffering of glutamate in neurones, was studied in neuroblastoma NB-2a cells. The accumulated KIC was mostly transaminated to leucine, while free keto-acid was detectable either only after prolonged times or after inhibiting transaminase with aminooxyacetate. Accumulation of KIC was found to be inhibited by other branched-chain ketoacids, while lactate and beta-hydroxybutyrate were ineffective. The transport of KIC, resembling a facilitated diffusion, was decreased by phloretin, alpha-cyano-4-hydroxycinnamate, 4,4'-diisothiocyano-2,2'-stilbenedisulphonate, and p-chlorimercuribenzoate. The process of accumulation did not resemble a symport with protons; therefore an involvement of the known proton-coupled monocarboxylate transporters (MCT) was excluded. Distribution of KIC suggests a mechanism involving a cotransport with 2 [Na+].

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1997

Evidence for an asymmetrical uptake of L-carnitine in the blood-brain barrier in vitro.

The transport of L-carnitine (4-N-trimethylammonium-3-hydroxybutyric acid) was studied with a primary culture of porcine brain capillary endothelial cells (BCEC) as an in vitro model of the blood-brain barrier. The measurements with suspended cells and cell monolayers allowed to distinguish a polarized transport phenomena. The part of the BCEC cells exposed to the medium (apical membrane) accumulated carnitine by a sodium-independent, saturable (Km=28 microM) system, with k=0.018 min-1. Exposure of the basolateral part revealed a presence of a facilitated diffusion process. Carnitine uptake through the saturable system was inhibited by butyrobetaine. Acylcarnitines and choline have no effect on the carnitine accumulation in suspended cells, a process diminished by phenylalanine, leucine, and L system inhibitor. This points to the possibility that carnitine enters through the basolateral membrane using amino acid transporting systems. A different, novel system is postulated to operate in the apical part of the plasma membrane of BCEC.

Animals↗
PubMed1999

The importance of L-phenylalanine transport and its autocrine turnover to L-tyrosine for melanogenesis in human epidermal melanocytes.

A comparative study of (14)C-labeled l-phenylalanine and (3)H-labeled L-tyrosine uptake in cultures of human melanocytes (n = 8) and keratinocytes (n = 2) identified a significantly more rapid active transport for L-phenylalanine in melanocytes, whereas the slower uptake of L-tyrosine followed a concentration-dependent gradient, confirming facilitated diffusion rather than active transport. In addition, a significantly more efficient autocrine turnover of L-phenylalanine to L-tyrosine via intracellular phenylalanine hydroxylase was demonstrated in melanocytes. The incorporation of the newly synthesized radiolabeled L-tyrosine was directly followed into the end product melanin. The presence of L-phenylalanine in the culture medium produced 40% more melanin compared to an equivalent concentration of L-tyrosine alone. The transport of extracellular L-phenylalanine and its intracellular metabolism to L-tyrosine via intracellular phenylalanine hydroxylase are coupled to calcium uptake/efflux, whereas L-tyrosine uptake is calcium independent. Taken together, our results identified for the first time the importance of autocrine calcium-dependent active l-phenylalanine uptake/turnover in melanocytes as a major pathway for melanogenesis.

Autocrine Communication↗
PubMed2000

Expression of ZRC1 coding for suppressor of zinc toxicity is induced by zinc-starvation stress in Zap1-dependent fashion in Saccharomyces cerevisiae.

The ZRC1 gene was cloned as a multicopy suppressor of zinc toxicity in Saccharomyces cerevisiae. Zrc1 belongs to CDF (cation diffusion facilitator) family. The transporters belonging to this family are thought to play an important role in metal detoxification. However, we found that cell growth of zrc1Delta mutant was lowered under the metal-limited conditions, which was restored by zinc. The Zap1 transcription factor is crucial for expression of several genes responsive to zinc-starvation stress. The expression of ZRC1 was induced in Zap1-dependent fashion when the intracellular zinc level was decreased and this induction was repressed by zinc. These results imply an important role of Zrc1 in the zinc-starvation stress.

Base Sequence↗
PubMed1994

The glucose transporter in the plasma membrane of the outer segments of bovine retinal rods.

The facilitated diffusion glucose transporter in the plasma membrane of intact outer segments isolated from bovine retinal rods (ROS) was characterized by measurements of: (1) 14C-labeled 3-O-methylglucose fluxes; and (2) glucose-sensitive binding of 3H-labeled cytochalasin B to ROS membranes. Inhibition of 3-O-methylglucose influx into ROS, inhibition of 3-O-methylglucose efflux from ROS and glucose-sensitive binding of cytochalasin B to ROS showed very similar cytochalasin B inhibition/dissociation constants of 0.9 microM, 1.3 microM and 1.3 microM, respectively. D-glucose inhibited both 14C-labeled 3-O-methylglucose transport and cytochalasin B binding. The above results suggest that D-glucose-sensitive cytochalasin B binding reflects specific binding to the ROS glucose transporter and the density of glucose transporter in the ROS plasma membrane was determined to be 800 microns-2, comparable to relatively abundant ROS plasma membrane proteins such as the cGMP-gated channel and the Na-Ca+K exchanger. Displacement of 3H-labeled cytochalasin B by non-transportable hexoses was used to localize the hexose transporters to the ROS plasma membrane and to examine a simple single-site, alternating conformation model for hexose transport. A comparison between the Glut1 glucose transporters of bovine ROS, bovine erythrocytes and human erythrocytes suggests that kinetic and pharmacological characteristics of glucose transporters cannot be predicted in a simple manner from gene type and species.

3-O-Methylglucose↗
PubMed2002

Oxytocin-secreting neurons: A physiological model of morphological neuronal and glial plasticity in the adult hypothalamus.

Oxytocin-secreting neurons of the hypothalamoneurohypophysial system undergo reversible morphological changes whenever they are strongly stimulated. In the hypothalamus, such structural plasticity is represented by modifications in the size and shape of their somata and dendrites, in the extent to which their surfaces are covered by glia, and in the density of their synapses. In the neurohypophysis, there is a parallel reduction in glial (pituicyte) coverage of their axons together, with retraction of pituicyte processes from the perivascular basal lamina and an increase in the number and size of their terminals. These changes occur rapidly, within a few hours. On the other hand, the system returns to its prestimulated condition on arrest of stimulation at a rate that depends on the length of time it has remained activated. Such neuronal-glial changes have several functional consequences. In the hypothalamic nuclei, reduction in astrocytic coverage of oxytocinergic neurons and their synapses modifies extracellular ionic homeostasis and glutamate clearance and, therefore, their overall excitability. Since it results in extensive dendritic bundling, it may also lead to ephaptic interactions and may facilitate dendritic electrotonic coupling. A most important indirect effect may be to permit synaptic remodeling that occurs concomitantly and that results in significant increases in the number of excitatory and inhibitory synapses driving their activity. In the stimulated neurohypophysis, glial retraction results in increased levels of extracellular K+ which can enhance neurohormone release while an enlarged neurovascular contact zone may facilitate diffusion of neurohormone into the circulation. Ongoing work aims to unravel the cell mechanisms and factors underlying such plasticity and has revealed that neurons and glia of the hypothalamoneurohypophysial system continue to express juvenile molecular features associated with similar neuronglial interactions and synaptic events during development and regeneration. They include strong expression of cell surface adhesion molecules like F3/contactin and polysialylated neural cell adhesion molecule, extracellular matrix glycoproteins like tenascin C, and cytoskeletal proteins like vimentin and microtubule-associated protein 1D. Some of these molecules reach the cell surface constitutively while others follow the activity-dependent regulated pathway. We consider many of these molecular features permissive, allowing oxytocin neurons and their glia to undergo morphological remodeling throughout life, provided the proper stimulus intervenes. In the hypothalamic nuclei, one such stimulus is centrally released oxytocin; in the neurohypophysis, an adrenergic, cAMP-mediated mechanism appears responsible.

Animals↗
PubMed1993

Isolation and sequencing of Escherichia coli gene proP reveals unusual structural features of the osmoregulatory proline/betaine transporter, ProP.

Transporters encoded in genetic loci putP, proP and proU mediate proline and/or betaine accumulation by Escherichia coli K-12. The ProP and ProU systems are osmoregulatory. Activation of ProP in response to hyperosmotic stress has been demonstrated both in vivo and in vitro. It therefore serves as a model experimental system for the analysis of osmosensory and osmoregulatory mechanisms. We developed methodologies which will facilitate the identification of proline transporter genes by functional complementation of putP proP proU bacteria. E. coli gene proP was isolated and located within a chromosomal DNA fragment. Deletion, complementation and sequence analysis revealed putative promoter and transcription termination signals flanking a 1500 base-pair open reading frame. The predicted 55 kDa ProP protein was hydrophobic. In vitro expression of proP yielded a protein whose apparent molecular mass was determined to be 42 kDa by polyacrylamide gel electrophoresis under denaturing conditions. Database searches and cluster analysis defined relationships among the ProP sequence and those of integral membrane proteins that comprise a transporter superfamily. Members of the superfamily catalyze facilitated diffusion or ion linked transport of organic solutes in prokaryotes and eukaryotes. Multiple alignment revealed particularly close correspondence among the ProP protein, citrate transporters from E. coli and Klebsiella pneumoniae and an alpha-ketoglutarate transporter from E. coli. The predicted ProP sequence differed from those closely similar sequences in possessing an extended central hydrophilic loop and a carboxyl terminal extension. Unlike other protein sequences within the transporter superfamily, the carboxyl terminal extension of ProP was strongly predicted to participate in formation of an alpha-helical coiled coil. These data suggest that the ProP protein catalyzes solute-ion cotransport. Its unusual structural features may be related to osmoregulation of its activity.

Amino Acid Sequence↗
PubMed1999

Nucleoside transporters of mammalian cells.

In this review, we have summarized recent advances in our understanding of the biology of nucleoside transport arising from new insights provided by the isolation and functional expression of cDNAs encoding the major nucleoside transporters of mammalian cells. Nucleoside transporters are required for permeation of nucleosides across biological membranes and are present in the plasma membranes of most cell types. There is growing evidence that functional nucleoside transporters are required for translocation of nucleosides between intracellular compartments and thus are also present in organellar membranes. Functional studies during the 1980s established that nucleoside transport in mammalian cells occurs by two mechanistically distinct processes, facilitated diffusion and Na(+)-nucleoside cotransport. The determination of the primary amino acid sequences of the equilibrative and concentrative transporters of human and rat cells has provided a structural basis for the functional differences among the different transporter subtypes. Although nucleoside transporter proteins were first purified from human erythrocytes a decade ago, the low abundance of nucleoside transporter proteins in membranes of mammalian cells has hindered analysis of relationships between transporter structure and function. The molecular cloning of cDNAs encoding nucleoside transporters and the development of heterologous expression systems for production of recombinant nucleoside transporters, when combined with recombinant DNA technologies, provide powerful tools for characterization of functional domains within transporter proteins that are involved in nucleoside recognition and translocation. As relationships between molecular structure and function are determined, it should be possible to develop new approaches for optimizing the transportability of nucleoside drugs into diseased tissues, for development of new transport inhibitors, including reagents that are targeted to the concentrative transporters, and, eventually, for manipulation of transporter function through an understanding of the regulation of transport activity.

Animals↗
PubMed1988

Color analysis method for studying oxygen transport in hemoglobin solutions using an image-input and -processing system.

A method for quantitative analysis of hemoglobin color to estimate the oxygen saturation was developed. The method uses an image-input and -processing system composed of a 3-tube video camera and a digital image analyzer. Using the system connected to a microscope, facilitated diffusion of oxygen in hemoglobin solutions was observed and analyzed in a position-sensitive way. The results confirmed its applicability to this study and gave information about the diffusion mechanism expressed by the empirical formula J = kY, where J is the flux of oxygen, Y is the oxygen saturation of hemoglobin, and k is a constant.

Colorimetry↗
PubMed1983

Direct measurement of intracellular O2 gradients; role of convection and myoglobin.

During steady phasic exercise in a red muscle the entire O2 gradient between capillary and mitochondria occurs as a step over less than 5 m. The magnitude of this step is determined by VO2 and capillary PO2, and is independent of distance from a capillary, or local capillary density. The above cannot be explained by ordinary and/or facilitated diffusion, according to a classical Krogh model. A step gradient can be produced by intracellular convection and Mb, acting in concert. A uniformly low cell PO2 maximizes the trans-capillary O2 gradient, and hence the O2 flux. Since the O2 affinity of Mb is about 50 times less than that cytochrome a, a3, mitochondria can respire maximally at tensions well below the Mb P50. It seems likely that the principal function of Mb during steady, phasic exercise is to compensate for short capillary transit times by accelerating O2 release from Hb.

Animals↗
PubMed1990

Facilitated transport of oxygen through hemoglobin solutions.

A method for quantitative analysis of hemoglobin color to estimate the oxygen saturation was developed. The method uses an image-input and -processing system composed of a 3-tube video camera and a digital image analyzer. When the system is connected to a microscope, the facilitated diffusion of oxygen in hemoglobin solutions can be observed and analyzed in a position-sensitive manner. The results led to a new transport model expressed as: J = k'CY/d, where J is the oxygen flux, C is the hemoglobin concentration, Y is the oxygen saturation of hemoglobin, d is the distance between the entrance of oxygen and the diffusion front, and k' is a constant.

Algorithms↗
PubMed2003

How proton translocation across mitochondrial inner membranes drives the Fo rotor of ATP synthase.

It has been believed for some time that there are two major but alternative models for the selective transport of ions across membranes generally. On the one hand this transport is by way of transmembrane channels. These channels exist within macromolecular complexes which span the membrane and provide a hydrophilic pathway through which the ions can be translocated. Alternatively, carriers have been postulated which can dissolve in the lipid moiety of the membrane, are able to selectively co-ordinate ions, and then move from one side of the membrane to the other, before unloading the ion. Proton translocation across the inner mitochondrial membrane is intensely interesting, firstly because the process is tightly coupled to the synthesis of ATP, but additionally because the emerging picture of proton translocation incorporates features from both the classical mechanisms of ion transport. Thus there are two channels, one from either side of the membrane, both of which penetrate to the centre of the membrane. However neither of them individually spans the membrane, but they remain separated by a short distance in the plane of the membrane. Transport across this remaining gap involves a carrier that reversibly binds the ion. The mechanism for transport across this remaining region is not carrier-facilitated diffusion, nor any "flip flop" change of shape by the carrier. Rather it is an electrically driven rotation of the carrier, and the source of the electric field that drives this rotor is the transmembrane electric potential.

Adenosine Diphosphate↗
PubMed1993

Filament overlap affects TnC extraction from skinned muscle fibres.

Recent studies on calcium regulation of muscle contraction selectively extract troponin C (TnC) from skinned skeletal muscle fibres with a low ionic strength rigor solution containing a Ca2+/Mg2+ chelator. As previous results from this laboratory and others demonstrate a crossbridge effect, especially rigor, on many of the properties of TnC, the effects of filament overlap on TnC extraction from skinned rabbit psoas muscle fibres were investigated. Tension-pCa relationships at a sarcomere length of 2.7 microns were determined before and after a 5 min TnC extraction at sarcomere lengths of 2.3, 2.5, 2.7, 3.1, 3.3 or 3.5 microns with 20 mM Tris, pH 7.8, 5 mM EDTA. The decrease in the post-extraction maximum Ca2+ activated tension, an indicator of the amount of TnC extracted, was linearly related to the overlap of the thick and thin filaments with decreases in tension being associated with a decrease in filament overlap. The smaller fibre diameter at the longer sarcomere length could facilitate diffusion of TnC from fibre segments. However, the wide range of measured diameters, 40-120 microns, accounted for only 14% of the observed tension decrement and shrinking the fibre with polyvinylpyrrolidone did not increase the tension decrement. Increasing the sarcomere length before extraction was also found to decrease the TnC content of fibre segments along with the post-extraction maximum tension. Thus, TnC appears to be preferentially extracted from non-overlap than overlap regions of the sarcomere. These results further indicate that rigor crossbridges affect TnC other than through increased Ca2+ binding and that under the conditions used here, they retard its extraction.

Animals↗
PubMed1995

Mutation of two conserved arginine residues in the glucose transporter GLUT4 supresses transport activity, but not glucose-inhibitable binding of inhibitory ligands.

Two arginine residues (RR333/334) in the conserved GRR motif located in the endofacial loop between helix 8 and 9 of the glucose transporter GLUT4 were substituted for leucine and alanine, respectively. Reconstituted glucose transport activity of the construct (GLUT4-RR333/4LA) expressed in COS-7 or LM(TK-) cells was less than 10% of that of the wild-type GLUT4. In contrast, binding of the inhibitory ligand cytochalasin B and glucose-inhibitable photolabeling with IAPS-forskolin were not significantly affected. Exchange of a histidine residue (H337Q) previously believed to be involved in the binding of inhibitory ligands failed to affect any of the investigated parameters. These data suggest that positive charges in the GRR motif at the cytoplasmic surface of the transporter participate in the conformational changes of the carrier protein during the process of facilitated diffusion.

Animals↗
PubMed1992

The effect of sodium iodate on the blood-retinal and blood-brain barriers.

Both active transport through and permeability of the blood-retinal barrier (BRB) are affected by sodium iodate, while the blood-brain barrier (BBB) is more resistant. We studied the effect of sodium iodate on facilitated diffusion through the two barriers. The retinal (RUI) and brain (BUI) uptake indices were determined for D-glucose and two neutral amino acids in normal and sodium iodate-treated rats. The integrity of the barriers was estimated by RUI and BUI for L-glucose and by measuring tissue uptake of L-glucose after an intravenous injection. We found that 30 mg/kg sodium iodate had no effect on transport through or permeability of the BBB, while 20 mg/kg significantly (P < 0.02) reduced transport of D-glucose, but not amino acids, through the BRB 1 h after injection. After 24 h both 20 mg/kg and 30 mg/kg sodium iodate caused a significant disruption of the BRB (P < 0.005 and P < 0.001, respectively). Thus, sodium iodate selectively affects the carrier for D-glucose in the BRB but not in the BBB. The presence of an epithelial part in the BRB, the retinal pigment epithelium, may explain the difference between the two barriers.

Animals↗
PubMed1990

Fluorinated anthracyclines: synthesis and biological activity.

A number of fluorine containing derivatives of daunomycin and Adriamycin have been synthesised with a fluorine substituent located on the C-9 side chain. They included the p-trifluoromethyl-(4) and p-fluorobenzoate (3) esters of Adriamycin and the trifluoro-ethyl-hydrazones of Adriamycin (2) and daunomycin (1). The less polar derivatives (esters 3 and 4) appear to enter HeLa cells more readily than the polar derivatives (hydrazones 1 and 2) as indicated by the rates and extent of cellular uptake and the uptake was by facilitated diffusion. All four fluorinated derivatives were less active than their parent anthracyclines, but the difference was less pronounced when considering specific potency. The fluorinated derivatives (1-4) behave sufficiently similar to daunomycin and Adriamycin to enable their use as fluorine probes in 19F NMR physicochemical and cellular studies of anthracyclines.

Antibiotics, Antineoplastic↗
PubMedDate not supplied

Topography and functions of sulfhydryl groups of the human erythrocyte glucose transport mechanism.

Membrane-impermeant and -permeant maleimides were applied to characterize the location and function of the sulfhydryl (SH) groups essential for the facilitated diffusion mediated by the human erythrocyte glucose transport protein. Three such classes have been identified. Type I SH is accessible to membrane-impermeant reagents at the outer (exofacial) surface of the intact erythrocyte. Alkylation of this class inhibits glucose transport; D-glucose and cytochalasin B protect against the alkylation. Type II SH is located at the inner (endofacial) surface of the membrane and is accessible to the membrane-impermeant reagent glutathione maleimide only after lysis of the erythrocyte. D-glucose enhances, while cytochalasin B reduces, the alkylation of Type II SH by maleimides. Reaction of Types I and II SH with an impermeant maleimide increases the half-saturation concentration for binding of D-glucose to erythrocyte membranes. By contrast, inactivation of Type III SH markedly decreases the half-saturation concentration for the binding of D-glucose and other transported sugars. Type III SH is inactivated by the relatively lipid-soluble reagents N-ethylmaleimide (NEM) and dipyridyl disulfide, but not by the impermeant glutathione maleimide. Type III SH is thus located in a hydrophobic membrane domain. A kinetic model constructed to explain these observations indicates that Type III SH is required for the translocation event in a hydrophobic membrane domain which leads to the dissociation of glucose bound to transport sites at the membrane surfaces.

Alkylation↗