Effects of 2,3-diphosphoglycerate and other organic phosphate compounds on oxygen affinity and intracellular pH of human erythrocytes

Duhm, Jochen

doi:10.1007/bf00586998

Cited by 165 publications

(52 citation statements)

References 31 publications

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“…However, as the Hbs of these two species have such low anion sensitivities, the dramatic reductions in intracellular DPG may not have important direct effects on the regulation of Hb-O 2 affinity during hibernation. Instead, the reduced DPG concentration may indirectly affect Hb-O 2 affinity by altering the Donnan equilibrium of protons across the red cell membrane, as the reduced intracellular concentration of non-diffusible anions produces a corresponding reduction in proton concentration (Duhm, 1971). The resulting increase in intracellular pH at a given plasma pH would then increase Hb-O 2 affinity via the pronounced Bohr effect of the sciurid Hbs (Fig.4).…”

Section: Discussionmentioning

confidence: 99%

Hemoglobin function and allosteric regulation in semi-fossorial rodents (family Sciuridae) with different altitudinal ranges

Revsbech

Tufts

Projecto-Garcia

et al. 2013

Journal of Experimental Biology

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SUMMARYSemi-fossorial ground squirrels face challenges to respiratory gas transport associated with the chronic hypoxia and hypercapnia of underground burrows, and such challenges are compounded in species that are native to high altitude. During hibernation, such species must also contend with vicissitudes of blood gas concentrations and plasma pH caused by episodic breathing. Here, we report an analysis of hemoglobin (Hb) function in six species of marmotine ground squirrels with different altitudinal distributions. Regardless of their native altitude, all species have high Hb-O 2 affinities, mainly due to suppressed sensitivities to allosteric effectors [2,3-diphosphoglycerate (DPG) and chloride ions]. This suppressed anion sensitivity is surprising given that all canonical anion-binding sites are conserved. Two sciurid species, the golden-mantled and thirteen-lined ground squirrel, have Hb-O 2 affinities that are characterized by high pH sensitivity and low thermal sensitivity relative to the Hbs of humans and other mammals. The pronounced Bohr effect is surprising in light of highly unusual amino acid substitutions at the C-termini that are known to abolish the Bohr effect in human HbA. Taken together, the high O 2 affinity of sciurid Hbs suggests an enhanced capacity for pulmonary O 2 loading under hypoxic and hypercapnic conditions, while the large Bohr effect should help to ensure efficient O 2 unloading in tissue capillaries. In spite of the relatively low thermal sensitivities of the sciurid Hbs, our results indicate that the effect of hypothermia on Hb oxygenation is the main factor contributing to the increased blood-O 2 affinity in hibernating ground squirrels.

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Section: Discussionmentioning

confidence: 99%

Hemoglobin function and allosteric regulation in semi-fossorial rodents (family Sciuridae) with different altitudinal ranges

Revsbech

Tufts

Projecto-Garcia

et al. 2013

Journal of Experimental Biology

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“…However, in humans and other mammals, the hypoxia-induced increase in red cell [DPG] continues at elevations well above the threshold at which further reductions in Hb-O 2 affinity become counterproductive due to arterial desaturation (Winslow et al, 1984;Samaja et al, 2003). Even when all Hb is fully liganded with DPG (at a DPG:Hb ratio of ≥2-3), further increases in [DPG] continue to indirectly reduce Hb-O 2 affinity because the increased erythrocytic concentration of non-diffusible anions reduces cellular pH, thereby reducing Hb-O 2 affinity via the Bohr effect (Duhm, 1971;Samaja and Winslow, 1979;Mairbäurl, 1994). Consequently, the increase in plasma pH caused by respiratory alkalosis has offsetting effects in mammalian red cells: the Bohr effect promotes an increased Hb-O 2 affinity, but this is counterbalanced by the increase in intracellular [DPG] (Winslow et al, 1984;Samaja et al, 1997).…”

Section: The Role Of Hb Isoform Switching In Hypoxia Adaptationmentioning

confidence: 99%

Hemoglobin–oxygen affinity in high-altitude vertebrates: is there evidence for an adaptive trend?

Storz

2016

Journal of Experimental Biology

112

100

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In air-breathing vertebrates at high altitude, fine-tuned adjustments in hemoglobin (Hb)-O 2 affinity provide an energetically efficient means of mitigating the effects of arterial hypoxemia. However, it is not always clear whether an increased or decreased Hb-O 2 affinity should be expected to improve tissue O 2 delivery under different degrees of hypoxia, due to the inherent trade-off between arterial O 2 loading and peripheral O 2 unloading. Theoretical results indicate that the optimal Hb-O 2 affinity varies as a non-linear function of environmental O 2 availability, and the threshold elevation at which an increased Hb-O 2 affinity becomes advantageous depends on the magnitude of diffusion limitation (the extent to which O 2 equilibration at the blood-gas interface is limited by the kinetics of O 2 exchange). This body of theory provides a framework for interpreting the possible adaptive significance of evolved changes in Hb-O 2 affinity in vertebrates that have colonized high-altitude environments. To evaluate the evidence for an empirical generalization and to test theoretical predictions, I synthesized comparative data in a phylogenetic framework to assess the strength of the relationship between Hb-O 2 affinity and native elevation in mammals and birds. Evidence for a general trend in mammals is equivocal, but there is a remarkably strong positive relationship between Hb-O 2 affinity and native elevation in birds. Evolved changes in Hb function in highaltitude birds provide one of the most compelling examples of convergent biochemical adaptation in vertebrates.

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“…Two methods for artificially increasing the red cell DPG content have been commonly used-incubation with IPP (DUHM, 1971; or DPP (BRISTOw et al, 1977) solution. However, it has been reported that IPP cannot be used in canine erythrocytes for this purpose.…”

Section: Discussionmentioning

confidence: 99%

“…A difficulty encountered in experimental approach to this problem is that in vitro or in vivo production of blood with low oxygen affinity is sometimes not so easy (TEISSEIRE et al, 1985). Incubation of red cells with inosine-pyruvate-inorganic phosphate (IPP) mixture (DUHM, 1971; has been most frequently used to stimulate the synthesis of red cell 2,3-diphosphoglycerate (DPG) which, in turn, exerts a potent in situ lowering effect upon the oxygen affinity (BENESCH and BENESCH, 1967;CHANUTIN and CURNISH, 1967). However, DPG in red cells of such animals as the dog and guinea pig, cannot be elevated by this method due to low permeability of the red cell membrane to these agents and/or metabolic peculiarity (DUHM,1974;MCMANUS,1974).…”

mentioning

confidence: 99%

Incubation procedure effective for decreasing oxygen affinity of red cells in the dog.

et al. 1986

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Because oxygen affinity of canine red cells had been hardly reduced by the conventional procedure of incubation with inosinepyruvate-phosphate or dihydroxyacetone-pyruvate-phosphate, incubation with acidified phosphoenolpyruvate (PEP) medium was tested for its effect on oxygen affinity. As this procedure had been shown to induce a significant increase of 2,3-diphosphoglycerate (DPG) in human red cells, it was also proved to be effective for lowering oxygen affinity of canine red cells. Incubation with 15 mM PEP in ACD medium (pH 6.0) at 37°C for 30 min was the standard procedure established after critical scrutiny. The incubated blood exhibited an average increase in half-saturation pressure (P50) amounting to 7 Torr (pH 7.40, P~02 40 Torr, 37°C), with no appreciable hemolysis and little change in mean corpuscular hemoglobin concentration. Results with Dowex 1-X8 anion exchange chromatography of acid soluble phosphates from the incubated red cells suggested that PEP penetrated rapidly through, the canine red cell membrane and was metabolized to DPG via the retrograde process of the Embden-Meyerhof glycolytic pathway.

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Effects of 2,3-diphosphoglycerate and other organic phosphate compounds on oxygen affinity and intracellular pH of human erythrocytes

Cited by 165 publications

References 31 publications

Hemoglobin function and allosteric regulation in semi-fossorial rodents (family Sciuridae) with different altitudinal ranges

Hemoglobin function and allosteric regulation in semi-fossorial rodents (family Sciuridae) with different altitudinal ranges

Hemoglobin–oxygen affinity in high-altitude vertebrates: is there evidence for an adaptive trend?

Incubation procedure effective for decreasing oxygen affinity of red cells in the dog.

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