scholarly journals Regulation of Extra- and Intracellular pH in the Brain in Severe Hypoglycemia

1981 ◽  
Vol 1 (1) ◽  
pp. 85-96 ◽  
Author(s):  
Dale Pelligrino ◽  
Bo K. Siesjö
Keyword(s):  
Intracellular Ph ◽  
Ph Regulation ◽  
Cell Damage ◽  
Energy State ◽  
Energy Charge ◽  
Severe Hypoglycemia ◽  
Cell Membrane Permeability ◽  
Adenylate Energy Charge ◽  
Acid Base ◽  
The Brain

Severe hypoglycemia is associated with a marked curtailment of cerebral glucose supply and with consumption of endogenous carbohydrate metabolites and amino acids, many of which exist as anions of acids. Since metabolic control of intracellular pH in acute hypo- and hypercapnia seems to be dependent on the production and consumption of metabolic acids, it must be suspected that intracellular pH in the brain is poorly regulated in hypoglycemic animals. We induced hypocapnia (Paco2 about 15 mm Hg) and hypercapnia (Paco2 about 90 mm Hg) in insulin-injected animals in “precoma” (EEG pattern of slow waves, polyspikes) and “coma” (cessation of EEG activity) and measured CSF and intracellular acid-base changes using the CO2 method. The induced hypoglycemia did not measurably alter CSF acid-base changes from the normal during hypercapnia, but it did impair CSF pH regulation in hypocapnia. Animals in precoma showed an unchanged cerebral energy state during both hypo- and hypercapnia. Regulation of intracellular pH was not measurably affected in hypercapnia but was reduced in hypocapnia. These results could be accounted for by a reduced ability of the hypoglycemic animals to produce metabolic acids in response to the decrease in Pco2, while the capacity to “consume” acids was largely retained. In comatose animals, cerebral energy state was held at normocapnic levels during hypercapnia but deteriorated during hypocapnia. In the latter condition, the reduction in adenylate energy charge correlated to a decrease in blood pressure. The capacity to alter metabolic acid levels was abolished. In spite of this, hypocapnia was associated with a marked rise in intracellular pH, in some animals to values of about 7.7 (control, 7.0), and hypercapnia caused only very moderate reduction in intracellular pH. It is proposed that the excessive increase in intracellular pH during hypocapnia was due to hypotension-induced energy failure with subsequent depolarization of cells and passive equilibration of HCO3− (or H+) across the cell membranes. In hypercapnia, the influx of HCO3− into cells was unrelated to further deterioration of cerebral energy state but could possibly have been caused by CO2-induced depolarization and/or increased cell membrane permeability to HCO3−/H+ ions. It is concluded that severe hypoglycemia disrupts intracellular pH regulation in the brain and that hypocapnia combined with moderate hypotension leads to an excessive intracellular alkalosis of potential importance for the development of cell damage.

The Effect of Combined Hypocapnia and Hypoxemia upon the Energy Metabolism of the Brain

1974 ◽  
Vol 52 (6) ◽  
pp. 1136-1146 ◽  
Author(s):  
V. MacMillan
Keyword(s):  
Energy Metabolism ◽  
Intracellular Ph ◽  
Tissue Oxygenation ◽  
Adenine Nucleotide ◽  
Energy State ◽  
Energy Charge ◽  
Tissue Levels ◽  
Hypoxic Brain ◽  
The Brain ◽  
Pyruvate Ratio

To evaluate whether hypocapnia affects the energy metabolism of the hypoxic brain, lightly anesthetized rats were maintained for 30 min at a [Formula: see text] of close to 30 mm Hg (1 mm Hg = 133 N/m2) and at [Formula: see text]'s of close to 35, 25, and 18 mm Hg, and compared with normoxic rats maintained at equivalent [Formula: see text]. The results showed that in hypoxic rats the energy state of the tissue, as evaluated from the adenylate contents and energy charge of the adenine nucleotide system, was adversely affected by exposures to [Formula: see text] of 18 mm Hg. The hypocapnia increased the accumulation of lactate during hypoxemia without altering the lactate/pyruvate ratio. Examination of the tissue levels of carbohydrate substrates, cerebral venous [Formula: see text], derived intracellular pH, and cytoplasmic NAD+/NADH ratios did not indicate that the increased tissue lactate accumulation was due to a further defect in tissue oxygenation. It is concluded that hypocapnia during hypoxemia is potentially detrimental.

scholarly journals The Boron & De Weer Model of Intracellular pH Regulation

2020 ◽  
Author(s):  
Rossana Occhipinti ◽  
Soroush Safaei ◽  
Peter J. Hunter ◽  
Walter F. Boron
Keyword(s):  
Cell Membrane ◽  
Intracellular Ph ◽  
Ph Regulation ◽  
Quantitative Model ◽  
Historical Background ◽  
Acid Base ◽  
Experimental Conditions ◽  
Subsequent Work ◽  
Energy Dependent ◽  
Parameter Values

The classic Boron & De Weer (1976) paper provided the first evidence of active regulation of pH} in cells by an energy-dependent acid-base transporter. These authors also developed a quantitative model --- comprising passive fluxes of acid-base equivalents across the cell membrane, intracellular reactions, and an active transport mechanism in the cell membrane (modelled as a proton pump) --- to help interpret their measurements of intracellular pH under perturbations of both extracellular CO2/HCO3- and extracellular NH3/NH4+. This Physiome paper seeks to make that model, and the experimental conditions under which it was developed, available in a reproducible and well-documented form, along with a software implementation that makes the model easy to use and understand. We have also taken the opportunity to update some of the units used in the original paper, and to provide a few parameter values that were missing in the original paper. Finally, we provide an historical background to the Boron & De Weer (1976) proposal for active pH regulation and a commentary on subsequent work that has enriched our understanding of this most basic aspect of cellular physiology.

scholarly journals American alligator (Alligator mississippiensis) embryos tightly regulate intracellular pH during a severe acidosis

2018 ◽  
Vol 96 (7) ◽  
pp. 723-727 ◽  
Author(s):  
R.B. Shartau ◽  
D.A. Crossley ◽  
Z.F. Kohl ◽  
R.M. Elsey ◽  
C.J. Brauner
Keyword(s):  
Intracellular Ph ◽  
Ph Regulation ◽  
Alligator Mississippiensis ◽  
American Alligator ◽  
Acid Base ◽  
Tissue Ph ◽  
Snapping Turtle ◽  
Blood Ph ◽  
Brain Ph

Crocodilian nests naturally experience high CO2 (hypercarbia), which leads to increased blood Pco2 and reduced blood pH (pHe) in embryos; their response to acid–base challenges is not known. During acute hypercarbia, snapping turtle embryos preferentially regulate tissue pH (pHi) against pHe reductions. This is proposed to be associated with CO2 tolerance in reptilian embryos and is not found in adults. In the present study, we investigated pH regulation in American alligator (Alligator mississippiensis (Daudin, 1802)) embryos exposed to 1 h of hypercarbia hypoxia (13 kPa Pco2, 9 kPa Po2). Hypercarbia hypoxia reduced pHe by 0.42 pH unit, while heart and brain pHi increased, with no change in the pHi of other tissues. The results indicate that American alligator embryos preferentially regulate pHi, similar to snapping turtle embryos, which represents a markedly different strategy of acid–base regulation than what is observed in adult reptiles. These findings suggest that preferential pHi regulation may be a strategy of acid–base regulation used by embryonic reptiles.

scholarly journals Intracellular pH regulation by acid-base transporters in mammalian neurons

2014 ◽  
Vol 5 ◽  
Author(s):  
Vernon A. Ruffin ◽  
Ahlam I. Salameh ◽  
Walter F. Boron ◽  
Mark D. Parker
Keyword(s):  
Intracellular Ph ◽  
Ph Regulation ◽  
Acid Base ◽  
Intracellular Ph Regulation

Metabolic regulation via intracellular pH

1984 ◽  
Vol 246 (4) ◽  
pp. R409-R438 ◽  
Author(s):  
W. B. Busa ◽  
R. Nuccitelli
Keyword(s):  
Cell Cycle ◽  
Intracellular Ph ◽  
Metabolic Regulation ◽  
Ph Dependence ◽  
Energy Charge ◽  
Adenylate Energy Charge ◽  
Potential Importance ◽  
Developmental Transitions ◽  
Cyclic Monophosphate ◽  
Stimulus Response

Despite earlier notions that intracellular pH (pHi) was invariant with time, recent studies have documented pHi changes of from 0.1 to 1.6 U during metabolic and developmental transitions in a variety of cells. Here we review the evidence for pHi-mediated regulation of gamete activation, cellular dormancy, the cell cycle, and stimulus-response coupling. Intracellular Ca2+ level changes also accompany many of these same transitions, and mounting evidence suggests that pHi and Ca2+ changes can be interdependent, both in their mechanisms and their effects. Although the significance of such interactions is still largely unclear, one example--the pronounced pH dependence of Ca2+ binding by calmodulin--suggests their potential importance in metabolic regulation. Similar evidence suggests that pHi changes also influence intracellular adenosine 3',5'-cyclic monophosphate levels, and vice versa. Finally we show that changes in adenylate energy charge can significantly alter pHi. In light of these interactions--and because pHi, unlike most other effectors, does not require specialized receptors--we suggest that pHi functions as a synergistic messenger, providing a metabolic context within and through which the actions of other effectors are integrated.

scholarly journals Regulatory adenylnucleotide-mediated binding of the PII-like protein SbtB to the cyanobacterial bicarbonate transporter SbtA is controlled by the cellular energy state

2021 ◽  
Author(s):  
Britta Förster ◽  
Bratati Mukherjee ◽  
Loraine Rourke ◽  
Joe A. Kaczmarski ◽  
Colin J. Jackson ◽  
...  
Keyword(s):  
Protein Function ◽  
Energy State ◽  
Energy Charge ◽  
Sensory Response ◽  
Adenylate Energy Charge ◽  
Higher Plant ◽  
Bicarbonate Transporter ◽  
Bicarbonate Transporters ◽  
Molecular Signals ◽  
Functional Analyses

ABSTRACTCyanobacteria have evolved one of the most powerful CO2 concentrating mechanisms (CCM), supporting high photosynthetic rates with limiting inorganic carbon (Ci), which makes their CCM a desirable system for integration into higher plant chloroplasts to enhance photosynthetic yield. The CCM is driven by active Ci uptake, facilitated by bicarbonate transporters and CO2 pumps, which locally elevates the CO2 concentration and carboxylation rate of the primary CO2 fixing enzyme, Rubisco, inside cytoplasmic micro-compartments (carboxysomes). Ci uptake responds allosterically to Ci supply and light, but the molecular signals and regulators of protein function are unknowns. Functional analyses of sodium-dependent bicarbonate transporters classified as SbtA in E. coli support the hypothesis that SbtA activity is negatively regulated through association with its cognate PII-like SbtB protein. Here, we demonstrate that the association of SbtA with SbtB from two phylogenetically distant species, Cyanobium sp. PCC7001 and Synechococcus elongatus PCC7942, depends on the relative amounts of ATP or cAMP compared to ADP or AMP. Higher ATP over ADP or AMP ratios decreased the formation of SbtA:SbtB complexes, consistent with a sensory response to the cellular adenylate energy charge (AEC=[ATP + 0.5 ADP]/[ATP+ADP+AMP]) and the different binding affinities of these adenylates to SbtB protein trimers. Based on evidence for adenylate ligand-specific conformation changes for the SbtB protein trimer of Cyanobium sp. PCC7001, we propose a role for SbtB as a curfew protein locking SbtA into an inactive state as safe-guard against energetically futile and physiologically disadvantageous activation during prolonged low cellular AEC and photosynthetically unfavourable conditions.

scholarly journals Role of Na-H exchangers and vacuolar H+ pumps in intracellular pH regulation in neonatal rat osteoclasts.

1995 ◽  
Vol 105 (2) ◽  
pp. 177-208 ◽  
Author(s):  
J H Ravesloot ◽  
T Eisen ◽  
R Baron ◽  
W F Boron
Keyword(s):  
Intracellular Ph ◽  
Imaging System ◽  
Ph Regulation ◽  
Neonatal Rat ◽  
Hill Coefficient ◽  
Acid Base ◽  
Buffering Power ◽  
Acid Extrusion

Osteoclasts resorb bone by pumping of H+ into a compartment between the cell and the bone surface. Intracellular pH (pHi) homeostasis requires that this acid extrusion, mediated by a vacuolar-type H+ ATPase, be complemented by other acid-base transporters. We investigated acid-extrusion mechanisms of single, freshly isolated, neonatal rat osteoclasts. Cells adherent to glass coverslips were studied in the nominal absence of CO2/HCO3-, using the pH-sensitive dye BCECF and a digital imaging system. Initial pHi averaged 7.31 and was uniform throughout individual cells. Intrinsic buffering power (beta 1) decreased curvilinearly from approximately 25 mM at pHi = 6.4 to approximately 6.0 mM at pHi = 7.4. In all polygonally shaped osteoclasts, and approximately 60% of round osteoclasts (approximately 20% of total), pHi recovery from acid loads was mediated exclusively by Na-H exchange. In these pattern-1 cells, pHi recovery was 95% complete within 200 s, and was blocked by removing Na+, or by applying 1 mM amiloride, 50 microM ethylisopropylamiloride (EIPA), or 50 microM hexamethyleneamiloride (HMA). The apparent K1/2 for HMA ([Na+]o = 150 mM) was 49 nM, and the apparent K1/2 for Na+ was 45 mM. Na-H exchange, corrected for amiloride-insensitive fluxes, was half maximal at pHi 6.73, with an apparent Hill coefficient for intracellular H+ of 2.9. Maximal Na-H exchange averaged 741 microM/s. In the remaining approximately 40% of round osteoclasts (pattern-2 cells), pHi recovery from acid loads was brisk even in the absence of Na+ or presence of amiloride. This Na(+)-independent pHi recovery was blocked by 7-chloro-4-nitrobenz-2-oxa-1,3-diazol (NBD-Cl), a vacuolar-type H+ pump inhibitor. Corrected for NBD-Cl insensitive fluxes, H+ pump fluxes decreased approximately linearly from 96 at pHi 6.8 to 11 microM/s at pHi 7.45. In approximately 45% of pattern-2 cells, Na+ readdition elicited a further pHi recovery, suggesting that H+ pumps and Na-H exchangers can exist simultaneously. We conclude that, under the conditions of our study, most neonatal rat osteoclasts express Na-H exchangers that are probably of the ubiquitous basolateral subtype. Some cells express vacuolar-type H+ pumps in their plasma membrane, as do active osteoclasts in situ.

Effects of in vivo and in vitro alkali treatment on intracellular pH regulation of OMCDis cells

1993 ◽  
Vol 265 (5) ◽  
pp. F729-F735
Author(s):  
M. Hayashi ◽  
M. Iyori ◽  
Y. Yamaji ◽  
T. Saruta
Keyword(s):  
Intracellular Ph ◽  
Cell Function ◽  
Ph Regulation ◽  
Alkali Treatment ◽  
Acid Base ◽  
Acetoxymethyl Ester ◽  
Functional Changes ◽  
Significant Difference

To examine functional changes of the transporters in the inner stripe of the outer medullary collecting ducts (OMCDis) by the peritubular acid-base status, in vitro microperfusion using the acetoxymethyl ester of 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein was performed. Cell alkalinization systems were assessed by the recovery rate (dpHi/dt) of intracellular pH (pHi) after intracellular acid loading by NH(4+)-NH3 prepulse with bath amiloride. In alkali-loaded rabbits (0.15 M NaHCO3 drinking for 14 days), dpHi/dt showed a significant decrease (1.80 +/- 0.29 pH units/s x 10(3)) compared with either control (3.30 +/- 0.59) or acid-loaded rabbits (0.15 M NH4Cl drinking for 14 days, 3.05 +/- 0.46). The difference of dpHi/dt between control and alkali-loaded rabbits was eliminated by lumen N-ethylmaleimide (NEM), suggesting that H+ pump activity was decreased. The effect of in vitro alkali treatment (50 mM HCO3-, pH 7.7) for 3-4 h was also examined. This incubation significantly decreased the dpHi/dt (1.83 +/- 0.35) compared with the time control experiments (3.18 +/- 0.28), whereas no significant difference was seen in the presence of lumen NEM. Anion exchanger activity, as determined from the pHi changes after Cl- addition to the bath, showed no significant change with in vivo or in vitro alkali treatment. The results indicate that cell function of the OMCDis is regulated in response to the peritubular acid-base environment via changes in the H(+)-adenosinetriphosphatase.

scholarly journals The Boron & De Weer Model of Intracellular pH Regulation

2020 ◽  
Author(s):  
Rossana Occhipinti ◽  
Soroush Safaei ◽  
Peter J. Hunter ◽  
Walter F. Boron
Keyword(s):  
Cell Membrane ◽  
Intracellular Ph ◽  
Ph Regulation ◽  
Quantitative Model ◽  
Historical Background ◽  
Acid Base ◽  
Experimental Conditions ◽  
Subsequent Work ◽  
Energy Dependent ◽  
Parameter Values

The classic Boron & De Weer (1976) paper provided the first evidence of active regulation of pH} in cells by an energy-dependent acid-base transporter. These authors also developed a quantitative model --- comprising passive fluxes of acid-base equivalents across the cell membrane, intracellular reactions, and an active transport mechanism in the cell membrane (modelled as a proton pump) --- to help interpret their measurements of intracellular pH under perturbations of both extracellular CO2/HCO3- and extracellular NH3/NH4+. This Physiome paper seeks to make that model, and the experimental conditions under which it was developed, available in a reproducible and well-documented form, along with a software implementation that makes the model easy to use and understand. We have also taken the opportunity to update some of the units used in the original paper, and to provide a few parameter values that were missing in the original paper. Finally, we provide an historical background to the Boron & De Weer (1976) proposal for active pH regulation and a commentary on subsequent work that has enriched our understanding of this most basic aspect of cellular physiology.

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