The air we breathe: three vital respiratory gases and the red blood cell: oxygen, nitric oxide, and carbon dioxide

Abstract

Three vital respiratory gases-oxygen (O(2)), nitric oxide (NO), and carbon dioxide (CO(2))-intersect at the level of the human red blood cell (RBC). In addition to hemoglobin (Hb)'s central role in O(2) transport, interaction of Hb with the Band 3 metabolon balances RBC energy flow. 2,3-Diphosphoglycerate enhances O(2) transport across the placenta and plays an important role in regulating RBC plasticity. NO is a key mediator of hypoxic vasodilation, but the precise role of RBC Hb remains controversial. In addition to established theories that depend on RBC uptake, delivery, and discharge of NO or its metabolites, an alternative hypothesis based on RBC permeability is suggested. NO depletion by free Hb may account for several clinical features seen during intravascular hemolysis or during deliberate infusion of Hb solutions used as RBC substitutes. CO(2) released by tissues triggers oxygen release through a series of well-coordinated reactions centered on the Band 3 metabolon. While RBC carbonic anhydrase and the Band 3 anion exchanger are central to this process, there is surprisingly little research on the kinetics of CO(2) clearance by transfusion. The three RBC gases are directly related to the three principal gases of Earth's atmosphere. Human fossil fuel consumption dumps 90 million metric tons of carbon into the atmosphere annually. Increasing CO(2) levels are linked to global warming, melting Arctic ice, rising sea levels, and climate instability. Just as individual cells depend on balance of the three vital gases, so too will their balance determine survival of life on Earth.

The Proteome of the Red Blood Cell: An Auspicious Source of New Insights into Membrane-Centered Regulation of Homeostasis

“…Observations such as these confirm and expand the hypotheses inspired from the proteomic inventories of red blood cells aged in vivo or in vitro [21,22,41]. It has been shown that oxygen-regulated association of key enzymes with the membrane regulates the activity of glycolysis and the pentose phosphate pathway, and that oxygen-mediated association of ankyrin with band 3 affects the binding between the cytoskeleton and the lipid bilayer [14,15,42]. Similarly, the association of proteins such as G protein subunits and activated forms of phosphorylating enzymes with membrane components, possibly linked to calcium-related signaling [43], are likely to constitute essential roles in the signaling networks regulating red blood cell homeostasis [5,22].…”

“…Phosphorylation-dependent association of key glycolytic enzymes with band 3 is part of the oxygen concentration-triggered regulation of ATP production and redox status, that may also regulate cell shape and deformability [14]. Data from labeling studies and pharmacological interventions in vitro suggest that a relationship between membrane organization and cytoplasmic protein association may not be restricted to band 3 and key glycolytic enzymes [15,16].…”

“…Comparative inventories of the red blood cell metabolome constitute the next phase in the translation of the proteomics data into functional information on the red blood cell metabolism. The close relationship between oxygen binding, ATP production, regulation of pH and redox status, and deformability [14] by itself warrants any attempt to a better understanding of its molecular foundation. Metabolomic data point towards genetically determined heterogeneity in the proteome, as apparent from the deduced activity of key enzymes of glycolysis and redox homeostasis [33].…”

Structure, function and applications of carbonic anhydrase isozymes

“…158 CO 2 is generated by all cells with an active Krebs cycle where it encounters RBC carbonic anhydrase, an essential RBC enzyme. 159,160 CA also provides substrate for anion exchanger (AE) protein, AE1, a plasma membrane Cl À /HCO À 3 exchanger of erythrocytes. This complex of CAII with AE1 has been proposed to maximize anion exchange activity.…”

Survival of red blood cells after transfusion: processes and consequences

“…Incorporation of the vesicle characteristics into the aging process supports the putative early involvement of hemoglobin, and the central role of band 3 in the aging process (Salzer et al, 2008; Willekens et al, 2008; Tissot et al, 2010; Bosman et al, 2012b). The cytoplasmic domain of band 3 is a central mediator of the concentration of ATP, 2,3-DPG, NADH and NADPH (Messana et al, 1996; Chu et al, 2008; Rogers et al, 2009; Dzik, 2011). Thereby, aging-associated changes in band 3 connect changes in cell morphology and volume, deformability, and interaction between cytoskeleton and lipid bilayer with changes in the activity of the glycolytic and the pentose phosphate pathways, and possibly ion transport and release of ATP and NO as well.…”