Erythrocytes circulating through the capillaries of the lung must exchange carbon dioxide (CO2) for oxygen (O2) during their short (0.5-1 sec.) transit time in pulmonary tissue (Reviewed in Jensen 2004, Esbaugh and Tufts 2006, Boron 2010). CO2 bound as carbamate to the N-terminus of hemoglobin and protons (H+) bound to histidine residues in hemoglobin are released as hemoglobin (HbA) binds O2. Bicarbonate (HCO3-) present in plasma is taken up by erythrocytes via the band3 anion exchanger (AE1, SLC4A1) and combined with H+ by carbonic anhydrases I and II (CA1/CA2) to yield water and CO2 (Reviewed by Esbaugh and Tufts 2006). CO2 is passively transported out of the erythrocyte by AQP1 and RhAG. HCO3- in plasma is also directly dehydrated by extracellular carbonic anhydrase IV (CA4) present on endothelial cells lining the capillaries in the lung.
Dash RK, Bassingthwaighte JB.; ''Erratum to: Blood HbO2 and HbCO2 dissociation curves at varied O2, CO2, pH, 2,3-DPG and temperature levels.''; PubMedEurope PMCScholia
Khalifah RG.; ''The carbon dioxide hydration activity of carbonic anhydrase. I. Stop-flow kinetic studies on the native human isoenzymes B and C.''; PubMedEurope PMCScholia
Boron WF.; ''Evaluating the role of carbonic anhydrases in the transport of HCO3--related species.''; PubMedEurope PMCScholia
Jensen FB.; ''Red blood cell pH, the Bohr effect, and other oxygenation-linked phenomena in blood O2 and CO2 transport.''; PubMedEurope PMCScholia
Murata K, Mitsuoka K, Hirai T, Walz T, Agre P, Heymann JB, Engel A, Fujiyoshi Y.; ''Structural determinants of water permeation through aquaporin-1.''; PubMedEurope PMCScholia
Simonsson I, Jonsson BH, Lindskog S.; ''A 13C nuclear magnetic resonance study of CO2/HCO-3 exchange catalyzed by human carbonic anhydrase I.''; PubMedEurope PMCScholia
Kalhoff H, Werkmeister F, Kiwull-Schöne H, Diekmann L, Manz F, Kiwull P.; ''The Haldane effect under different acid-base conditions in premature and adult humans.''; PubMedEurope PMCScholia
Zhu XL, Sly WS.; ''Carbonic anhydrase IV from human lung. Purification, characterization, and comparison with membrane carbonic anhydrase from human kidney.''; PubMedEurope PMCScholia
Wistrand PJ, Carter ND, Conroy CW, Mahieu I.; ''Carbonic anhydrase IV activity is localized on the exterior surface of human erythrocytes.''; PubMedEurope PMCScholia
Tibell L, Forsman C, Simonsson I, Lindskog S.; ''Anion inhibition of CO2 hydration catalyzed by human carbonic anhydrase II. Mechanistic implications.''; PubMedEurope PMCScholia
de Groot BL, Engel A, Grubmüller H.; ''A refined structure of human aquaporin-1.''; PubMedEurope PMCScholia
Morrow JS, Keim P, Visscher RB, Marshall RC, Gurd FR.; ''Interaction of 13 CO 2 and bicarbonate with human hemoglobin preparations.''; PubMedEurope PMCScholia
Jones GL, Shaw DC.; ''A chemical and enzymological comparison of the common major human erythrocyte carbonic anhydrase II, its minor component, and a new genetic variant, CA II Melbourne (237 Pro leads to His).''; PubMedEurope PMCScholia
Kraan J, Rispens P.; ''Contribution of the Haldane effect to the increase in arterial carbon dioxide tension in hypoxaemic subjects treated with oxygen.''; PubMedEurope PMCScholia
Blank ME, Ehmke H.; ''Aquaporin-1 and HCO3(-)-Cl- transporter-mediated transport of CO2 across the human erythrocyte membrane.''; PubMedEurope PMCScholia
Okuyama T, Waheed A, Kusumoto W, Zhu XL, Sly WS.; ''Carbonic anhydrase IV: role of removal of C-terminal domain in glycosylphosphatidylinositol anchoring and realization of enzyme activity.''; PubMedEurope PMCScholia
Esbaugh AJ, Tufts BL.; ''The structure and function of carbonic anhydrase isozymes in the respiratory system of vertebrates.''; PubMedEurope PMCScholia
Pinder JC, Pekrun A, Maggs AM, Brain AP, Gratzer WB.; ''Association state of human red blood cell band 3 and its interaction with ankyrin.''; PubMedEurope PMCScholia
Dahl NK, Jiang L, Chernova MN, Stuart-Tilley AK, Shmukler BE, Alper SL.; ''Deficient HCO3- transport in an AE1 mutant with normal Cl- transport can be rescued by carbonic anhydrase II presented on an adjacent AE1 protomer.''; PubMedEurope PMCScholia
Innocenti A, Firnges MA, Antel J, Wurl M, Scozzafava A, Supuran CT.; ''Carbonic anhydrase inhibitors: inhibition of the membrane-bound human isozyme IV with anions.''; PubMedEurope PMCScholia
Tazawa H, Mochizuki M, Tamura M, Kagawa T.; ''Quantitative analyses of the CO2 dissociation curve of oxygenated blood and the Haldane effect in human blood.''; PubMedEurope PMCScholia
Baird TT, Waheed A, Okuyama T, Sly WS, Fierke CA.; ''Catalysis and inhibition of human carbonic anhydrase IV.''; PubMedEurope PMCScholia
Morrow JS, Matthew JB, Wittebort RJ, Gurd FR.; ''Carbon 13 resonances of 13CO2 carbamino adducts of alpha and beta chains in human adult hemoglobin.''; PubMedEurope PMCScholia
Taylor AM, Boulter J, Harding SE, Cölfen H, Watts A.; ''Hydrodynamic properties of human erythrocyte band 3 solubilized in reduced Triton X-100.''; PubMedEurope PMCScholia
Endeward V, Cartron JP, Ripoche P, Gros G.; ''RhAG protein of the Rhesus complex is a CO2 channel in the human red cell membrane.''; PubMedEurope PMCScholia
Okuyama T, Sato S, Zhu XL, Waheed A, Sly WS.; ''Human carbonic anhydrase IV: cDNA cloning, sequence comparison, and expression in COS cell membranes.''; PubMedEurope PMCScholia
Musa-Aziz R, Chen LM, Pelletier MF, Boron WF.; ''Relative CO2/NH3 selectivities of AQP1, AQP4, AQP5, AmtB, and RhAG.''; PubMedEurope PMCScholia
Pesando JM.; ''Proton magnetic resonance studies of carbonic anhydrase. II. Group controlling catalytic activity.''; PubMedEurope PMCScholia
Ren X, Lindskog S.; ''Buffer dependence of CO2 hydration catalyzed by human carbonic anhydrase I.''; PubMedEurope PMCScholia
Ghannam AF, Tsen W, Rowlett RS.; ''Activation parameters for the carbonic anhydrase II-catalyzed hydration of CO2.''; PubMedEurope PMCScholia
Endeward V, Cartron JP, Ripoche P, Gros G.; ''Red cell membrane CO2 permeability in normal human blood and in blood deficient in various blood groups, and effect of DIDS.''; PubMedEurope PMCScholia
Salhany JM, Cordes KA, Sloan RL.; ''Gel filtration chromatographic studies of the isolated membrane domain of band 3.''; PubMedEurope PMCScholia
Doyle ML, Di Cera E, Robert CH, Gill SJ.; ''Carbon dioxide and oxygen linkage in human hemoglobin tetramers.''; PubMedEurope PMCScholia
Knauf PA, Gasbjerg PK, Brahm J.; ''The asymmetry of chloride transport at 38 degrees C in human red blood cell membranes.''; PubMedEurope PMCScholia
Ferguson JK, Roughton FJ.; ''The chemical relationships and physiological importance of carbamino compounds of CO(2) with haemoglobin.''; PubMedEurope PMCScholia
Mertzlufft F, Brandt L.; ''Hyperoxic intubation apnoea: an in vivo model for the proof of the Christiansen-Douglas-Haldane effect.''; PubMedEurope PMCScholia
Nakhoul NL, Davis BA, Romero MF, Boron WF.; ''Effect of expressing the water channel aquaporin-1 on the CO2 permeability of Xenopus oocytes.''; PubMedEurope PMCScholia
Endeward V, Musa-Aziz R, Cooper GJ, Chen LM, Pelletier MF, Virkki LV, Supuran CT, King LS, Boron WF, Gros G.; ''Evidence that aquaporin 1 is a major pathway for CO2 transport across the human erythrocyte membrane.''; PubMedEurope PMCScholia
Sterling D, Reithmeier RA, Casey JR.; ''A transport metabolon. Functional interaction of carbonic anhydrase II and chloride/bicarbonate exchangers.''; PubMedEurope PMCScholia
Walz T, Hirai T, Murata K, Heymann JB, Mitsuoka K, Fujiyoshi Y, Smith BL, Agre P, Engel A.; ''The three-dimensional structure of aquaporin-1.''; PubMedEurope PMCScholia
Klocke RA.; ''Mechanism and kinetics of the Haldane effect in human erythrocytes.''; PubMedEurope PMCScholia
Kernohan JC, Roughton FJ.; ''Thermal studies of the rates of the reactions of carbon dioxide in concentrated haemoglobin solutions and in red blood cells. A. The reactions catalysed by carbonic anhydrase. B. The carbamino reactions of oxygenated and deoxygenated haemoglobin.''; PubMedEurope PMCScholia
The binding of oxygen (O2) to hemoglobin (HbA) decreases the affinity of HbA for protons (H+) bound at histidine residues and carbon dioxide (CO2) bound chemically as a carbamate at the N-terminus of the HbA (Ferguson and Roughton 1934, Kernohan & Roughton 1968, Klocke 1973, Morrow et al. 1973, Morrow et al. 1976, Tazawa et al. 1983, Kraan & Rispens 1985, Doyle et al. 1987, Mertzlufft & Brandt 1989, Kalhoff et al.1994, Dash & Bassingthwaighte 2010, reviewed in Jensen 2004). This property of HbA is known as the Haldane Effect and facilitates the exchange of CO2 for O2 in the lungs.
Carbonic anhydrase IV (CA4) located on the extracellular face of the plasma membrane (Wistrand et al. 1999) dehydrates bicarbonate (HCO3--) to yield water and carbon dioxide (CO2) (Zhu & Sly 1990, Okayuma et al. 1992, Baird et al. 1997, Innocenti et al. 2004, reviewed in Lindskog 1997). Depending on the concentrations of reactants the reaction is reversible.
Carbonic anhydrase I (CA1, Khalifah 1971, Pesando 1975, Simonsson et al. 1982, Ren & Lindskog 1992) and carbonic anhydrase II (CA2, Tibell et al. 1984, Jones & Shaw 1983, Ghannam et al. 1986) hydrate carbon dioxide (CO2) to yield bicarbonate (HCO3-) and a proton (H+). During the reaction a hydroxyl group bound by the zinc ion (Zn2+) attacks the CO2 molecule in the active site to directly form HCO3- (reviewed in Lindskog 1997). The HCO3- is displaced by water, which is then deprotonated by a histidine residue to recreate the Zn2+:hydroxyl group. Depending on the concentrations of reactants the reaction is reversible.
The band 3 anion exchange protein (AE1, SLC4A1) exchanges chloride (Cl-) for bicarbonate (HCO3-) across the plasma membrane according to the concentration gradients of the anions (Knauf et al. 1996, Dahl et al. 2003). SLC4A1 may be part of a complex ("metabolon") with carbonic anhydrase II (CA2) which would facilitate the transport of HCO3- (Sterling et al. 2001).
Aquaporin-1 (AQP1) passively transports carbon dioxide (CO2) across the plasma membrane according to the concentration gradient (Nakhoul et al. 1998, Blank & Ehmke et al. 2003, Endeward et al. 2006, Musa-Aziz et al. 2009). The pore in AQP1 that conducts CO2 may be distinct from the pore that conducts water.
The Rhesus blood group type A glycoprotein (RhAG) passively transports carbon dioxide (CO2) across the plasma membrane according to the concentration gradient (Endeward et al. 2006, Endeward et al. 2008, Musa-Aziz et al. 2009).
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