PMC:6194691 / 171059-177168
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/6194691","sourcedb":"PMC","sourceid":"6194691","source_url":"https://www.ncbi.nlm.nih.gov/pmc/6194691","text":"Achieving a net flux: glucose as an example\nThere is regulation of transport across the blood–brain barrier both for glucose and for ions like Na+, K+ or Cl−. Regulation of glucose transport serves primarily to achieve the correct flux to support metabolism whereas regulation of ion transport is important to maintain the correct concentrations in extracellular fluid. The actual glucose concentration in ISF is relatively unimportant so long as it remains well above the Km for hexokinase (0.04–0.05 mM, see Sect. 5.3) but low enough to avoid formation of unwanted glycation products. The requirements for the regulation of the glucose transporter, GLUT1, were considered in detail by Barros et al. [314] and Simpson et al. [315]. Thus this section considers only the principles and the extent to which regulation can be obtained by altering glucose efflux.\nGLUT1 transport across the blood–brain barrier must be capable of producing a net flux that is equal to the cerebral metabolic rate for glucose, CMRglc, at all times both at rest and during nervous activity. Furthermore the system must be capable of increasing net flux quickly to match demand. If the net inward flux were not increased, then for a glucose content in brain of 1.3 mM × 0.77 mL g−1 and an increase in glucose consumption rate of 0.65 µmol g−1 min−1 (i.e. to twice resting level, figures for rats), the entire glucose reserve would be consumed in \u003c 2 min.\nCMRglc of stimulated nervous tissue isn’t easy to measure, partly because a region large enough to assay is likely to contain both stimulated and unstimulated tissue. Using quantitative autoradiography in rats exposed to monotonic sounds, Cruz et al. [517] were able to see as much as 85% increase in CMRglc in tonotopic bands of the inferior colliculus. Using PET imaging in human subjects viewing a reversing checkerboard pattern, Fox et al. [518] saw 50% increases in the visual cortex. Using measured arterio-venous concentration differences in human volunteers undergoing exhausting cycling or rowing exercise, Quistorff et al. ([353], data from [519]) found more than twofold increases in glucose uptake rate across the blood–brain barrier. (There was also a substantial uptake of lactate). From these and other studies, in order to support nervous activity it must be possible to increase the net flux across the blood–brain barrier by at least twofold within a few minutes.\nThere are three important steps in the delivery of glucose: arrival in the blood; net transport across the blood–brain barrier; subsequent diffusion to the sites of hexokinase. At rest, the blood flow delivers 5–10 times more glucose than does the net flux across the blood–brain barrier into the parenchyma. As a consequence the glucose concentrations in arterial blood and the capillaries are similar, and increasing blood flow can only produce modest changes in capillary concentration and the net inward flux into the parenchyma. Both diffusion within the parenchyma and transport across astrocyte and neuron membranes have been found to be fast (see Sect. 5.3). Thus the rate-limiting step in delivery of glucose to regions where it is required in the parenchyma is its transfer across the blood–brain barrier.\nIncreased glucose consumption by cells within the parenchyma will reduce glucose cisf and so reduce glucose efflux, resulting in increased net inward flux. Because the Michaelis–Menten constant, Km, for hexokinase is so low, the concentrations of glucose inside the cells and in ISF can be reduced to values much smaller than that found during times of low nervous activity. The size of this effect can be seen in the data of Betz et al. [327] as described in Appendix D. From that analysis there would be an increase of about 40% in the net inward flux, even if there were no change in transport capacity.22 Decreased glucose efflux is an important part of the response to increased nervous activity but it is not sufficient on its own to support demand [314, 315, 322]. Decreased efflux has the advantage that it occurs rapidly with the increase in glucose demand.\nChanges in GLUT1 transporter expression have been documented and reviewed elsewhere [322, 336, 520]. However, such changes are too slow to provide minute to minute changes in response to nervous activity. As discussed by Cura et al. [322] there are two types of changes that may occur quickly (see following), one is recruitment of additional preformed GLUT1 from intracellular stores and the other is an increase in transport rate for the existing GLUT1. Both may be occurring. There are suggestions that these changes may result in large effects, but there is no clear evidence of which if any are important at the blood–brain barrier.\nWith regard to GLUT1 recruitment to the cell surface, it can be detected not only on the luminal and abluminal membranes but also on vesicle membranes within the cytoplasm of brain endothelial cells [521]. Early studies on recruitment in a number of tissues were reviewed by Carruthers [328]. Subsequently it has been found that activation of AMP protein kinase (AMPK) by AMP when AMP is produced from ATP in response to nerve activity can in turn lead to recruitment to the cell surface. With cell culture systems including brain endothelial cells recruitment in response to AMP can be large, resulting in a two to threefold increase in GLUT1 at the plasma membrane [322, 522, 523].\nWith regard to modification of GLUT1 transport rate, it is known from studies on red blood cells that GLUT1 can be substantially inhibited by binding of ATP, an effect that is inhibited by AMP. When ATP hydrolysis is stimulated, ATP concentrations decrease and AMP concentrations increase, both of these events acting to release inhibition of GLUT1 [322, 524]. This effect can be large, a four to tenfold increase in glucose transport. Because increased AMP can increase both recruitment and activity of GLUT1 at the cell surface, it is easily imagined that small changes in AMP levels in endothelial cells could increase glucose transport sufficiently to support increased nervous 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