Quantitative Determination of Luminal and Abluminal Membrane Distributions of Transporters in Porcine Brain Capillaries by Plasma Membrane Fractionation and Quantitative Targeted Proteomics

Kubo, Yoshiyuki; Ohtsuki, Sumio; Uchida, Yasuo; Terasaki, Tetsuya

doi:10.1002/jps.24398

Cited by 71 publications

(90 citation statements)

References 48 publications

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“…Glucose transport across the blood–brain barrier is passive but mediated by specific, saturable GLUT1 transporters expressed in both the luminal and abluminal membranes of the endothelial cells [95–98]. Substantial amounts of the transporters are also found within the endothelial cell cytoplasm [99], presumably on vesicular membranes acting as a reservoir (see below).…”

Section: Transfers Of Water O2 Co2 and Major Nutrients Between Bloomentioning

confidence: 99%

See 1 more Smart Citation

Fluid and ion transfer across the blood–brain and blood–cerebrospinal fluid barriers; a comparative account of mechanisms and roles

Hladky

Barrand

2016

Fluids Barriers CNS

221

253

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The two major interfaces separating brain and blood have different primary roles. The choroid plexuses secrete cerebrospinal fluid into the ventricles, accounting for most net fluid entry to the brain. Aquaporin, AQP1, allows water transfer across the apical surface of the choroid epithelium; another protein, perhaps GLUT1, is important on the basolateral surface. Fluid secretion is driven by apical Na+-pumps. K+ secretion occurs via net paracellular influx through relatively leaky tight junctions partially offset by transcellular efflux. The blood–brain barrier lining brain microvasculature, allows passage of O2, CO2, and glucose as required for brain cell metabolism. Because of high resistance tight junctions between microvascular endothelial cells transport of most polar solutes is greatly restricted. Because solute permeability is low, hydrostatic pressure differences cannot account for net fluid movement; however, water permeability is sufficient for fluid secretion with water following net solute transport. The endothelial cells have ion transporters that, if appropriately arranged, could support fluid secretion. Evidence favours a rate smaller than, but not much smaller than, that of the choroid plexuses. At the blood–brain barrier Na+ tracer influx into the brain substantially exceeds any possible net flux. The tracer flux may occur primarily by a paracellular route. The blood–brain barrier is the most important interface for maintaining interstitial fluid (ISF) K+ concentration within tight limits. This is most likely because Na+-pumps vary the rate at which K+ is transported out of ISF in response to small changes in K+ concentration. There is also evidence for functional regulation of K+ transporters with chronic changes in plasma concentration. The blood–brain barrier is also important in regulating HCO3 − and pH in ISF: the principles of this regulation are reviewed. Whether the rate of blood–brain barrier HCO3 − transport is slow or fast is discussed critically: a slow transport rate comparable to those of other ions is favoured. In metabolic acidosis and alkalosis variations in HCO3 − concentration and pH are much smaller in ISF than in plasma whereas in respiratory acidosis variations in pHISF and pHplasma are similar. The key similarities and differences of the two interfaces are summarized.

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Section: Transfers Of Water O2 Co2 and Major Nutrients Between Bloomentioning

confidence: 99%

“…[318]), it was far from clear that Na + , K + -ATPase expression was predominantly at the abluminal surface [98]. Given these conflicting results the exact sidedness of the Na + -pump remains an unresolved issue.…”

Section: Ion and Fluid Transport At The Blood–brain Barriermentioning

confidence: 99%

Fluid and ion transfer across the blood–brain and blood–cerebrospinal fluid barriers; a comparative account of mechanisms and roles

Hladky

Barrand

2016

Fluids Barriers CNS

221

253

View full text Add to dashboard Cite

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“…We did not see vWF staining in the pericytes. Published studies report GLUT1 staining in cerebral microvessels is luminal dominant, abluminal dominant, or relatively equally distributed [23][24][25][26] (and references therein). The conflicting reports are, at least in part, due to differences in measurement technique and antibodies used.…”

Section: Validation Of Sample Integritymentioning

confidence: 99%

P-glycoprotein traffics from the nucleus to the plasma membrane in rat brain endothelium during inflammatory pain

Tome

Herndon

Schaefer

et al. 2016

J Cereb Blood Flow Metab

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P-glycoprotein (PgP), a drug efflux pump in blood-brain barrier endothelial cells, is a major clinical obstacle for effective central nervous system drug delivery. Identifying PgP regulatory pathways that can be exploited clinically is critical for improving central nervous system drug delivery. We previously found that PgP activity increases in rat brain microvessels concomitant with decreased central nervous system drug delivery in response to acute peripheral inflammatory pain. In the current study, we tested the hypothesis that PgP traffics to the luminal plasma membrane of the microvessel endothelial cells from intracellular stores during peripheral inflammatory pain. Using immunofluorescence microscopy, we detected PgP in endothelial cell nuclei and in the luminal plasma membrane in control animals. Following peripheral inflammatory pain, luminal PgP staining increased while staining in the nucleus decreased. Biochemical analysis of nuclear PgP content confirmed our visual observations. Peripheral inflammatory pain also increased endothelial cell luminal staining of polymerase 1 and transcript release factor/cavin1 and serum deprivation response protein/cavin2, two caveolar scaffold proteins, without changing caveolin1 or protein kinase C delta binding protein/cavin3 location. Our data (a) indicate that PgP traffics from stores in the nucleus to the endothelial cell luminal membrane in response to peripheral inflammatory pain; (b) provide an explanation for our previous observation that peripheral inflammatory pain inhibits central nervous system drug uptake; and (c) suggest a novel regulatory mechanism for PgP activity in rat brain. KeywordsCaveolin1, P-glycoprotein, protein kinase C delta binding protein/cavin3, polymerase 1 and transcript release factor/ cavin1, serum deprivation response protein/cavin2, trafficking

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“…GLUT1 has a high affinity for glucose (Heyes, 2010) and is also capable of transporting other hexose at a much-reduced rate (Gould et al, 1991). GLUT1 appears to be more prevalent on the luminal membrane of the vascular epithelium compared to the abluminal side (Farrell and Pardridge, 1991; Simpson et al, 2001; Cornford and Hyman, 2005; Kubo et al, 2015), though the exact ratio and distribution is debated (Farrell and Pardridge, 1991; Akiyoshi et al, 1999). This asymmetrical distribution of GLUT1 and the presence of hexokinase within the cells suggest that glucose is mostly transferred unidirectionally from blood to brain even though, given greater brain glucose concentrations, glucose could be transported from brain to blood.…”

Section: Introductionmentioning

confidence: 99%

“…The transport of these other monocarboxylates, however, occurs at a lower rate (Halestrap and Price, 1999; Juel and Halestrap, 1999; Halestrap and Wilson, 2012). In contrast to GLUT1, MCT1 appears to be equally distributed between the luminal and the abluminal membrane of epithelial cells (Leino et al, 1999; Kubo et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

Effects of Systemic Metabolic Fuels on Glucose and Lactate Levels in the Brain Extracellular Compartment of the Mouse

et al. 2017

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Classic neuroenergetic research has emphasized the role of glucose, its transport and its metabolism in sustaining normal neural function leading to the textbook statement that it is the necessary and sole metabolic fuel of the mammalian brain. New evidence, including the Astrocyte-to-Neuron Lactate Shuttle hypothesis, suggests that the brain can use other metabolic substrates. To further study that possibility, we examined the effect of intraperitoneally administered metabolic fuels (glucose, fructose, lactate, pyruvate, ß-hydroxybutyrate, and galactose), and insulin, on blood, and extracellular brain levels of glucose and lactate in the adult male CD1 mouse. Primary motor cortex extracellular levels of glucose and lactate were monitored in freely moving mice with the use of electrochemical electrodes. Blood concentration of these same metabolites were obtained by tail vein sampling and measured with glucose and lactate meters. Blood and extracellular fluctuations of glucose and lactate were monitored for a 2-h period. We found that the systemic injections of glucose, fructose, lactate, pyruvate, and ß-hydroxybutyrate increased blood lactate levels. Apart for a small transitory rise in brain extracellular lactate levels, the main effect of the systemic injection of glucose, fructose, lactate, pyruvate, and ß-hydroxybutyrate was an increase in brain extracellular glucose levels. Systemic galactose injections produced a small rise in blood glucose and lactate but almost no change in brain extracellular lactate and glucose. Systemic insulin injections led to a decrease in blood glucose and a small rise in blood lactate; however brain extracellular glucose and lactate monotonically decreased at the same rate. Our results support the concept that the brain is able to use alternative fuels and the current experiments suggest some of the mechanisms involved.

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Quantitative Determination of Luminal and Abluminal Membrane Distributions of Transporters in Porcine Brain Capillaries by Plasma Membrane Fractionation and Quantitative Targeted Proteomics

Cited by 71 publications

References 48 publications

Fluid and ion transfer across the blood–brain and blood–cerebrospinal fluid barriers; a comparative account of mechanisms and roles

Fluid and ion transfer across the blood–brain and blood–cerebrospinal fluid barriers; a comparative account of mechanisms and roles

P-glycoprotein traffics from the nucleus to the plasma membrane in rat brain endothelium during inflammatory pain

Effects of Systemic Metabolic Fuels on Glucose and Lactate Levels in the Brain Extracellular Compartment of the Mouse

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