This chapter is most relevant to Section F8(ii) from the 2017 CICM Primary Syllabus, which expects the exam candidates to be able to "describe the carbon dioxide carriage in blood including the Haldane effect and the chloride shift". Presumably, the Bohr effect was left out because it is an implied element, because surely you could not have a discussion of the Haldane effect without it. In any case, to know this in any great detail is probably not essential, as it has never been examined in the written paper.
- The Bohr effect describes the decrease in the oxygen affinity of haemoglobin in the presence of low pH or high CO2
- pH and CO2 both have effects on the haemoglobin tetramer:
- At a low pH, the histidine residues on one haemoglobin dimer become protonated, which permits the fomration of a "salt bridge" between dimers
- The formation of this bond stabilises the deoxygenated T-state
- The bond cannot form at a higher pH
- At a high CO2, CO2 binds to terminal amino groups and forms negatively charged carbamate groups
- These carbamate groups also stabilise the deoxygenated T-state of the haemoglobin tetramer by forming bonds with the positively charged amino groups on the opposite dimer
- Thus, both pH and CO2 stabilise the deoxyhaemoglobin molecule and decrease its affinity for oxygen, which facilitates the release of oxygen in the peripheral tissues.
- Quantitatively, the changes in pH play a greater role in changing the shape of the oxygen-haemoglobin disscoiation curve than do the changes in CO2
In the absence of an official definition, at a basic level one can define the Bohr effect as:
The decrease in the oxygen affinity of haemoglobin in the presence of low pH or high CO2
This is the consequence of the changes in the pKa of different amino acid residues, which occurs as the result of the haemoglobin tetramer undergoing conformational changes. As such, it is the other side of the same physicochemical coin as the Haldane effect: the Bohr effect is what happens to oxygen when CO2 stabilises the deoxygenated haemoglobin molecule, whereas the Haldane effect is what happens to CO2 when the haemoglobin molecule is deoxygenated.
The Bohr effect is usually described as "a decrease in oxygen affinity", but realistically it could refer to both the decreased affinity in acidic hypercapnic environments just as easily as to the increase in affinity seen in alkaline hypocapnic environments. For example, the latter is seen as the second Bohr effect in the "double Bohr effect" observed in the placenta.
Beyond that, there is also often mention of the "alkaline Bohr effect" and "acid Bohr effect", which are used to describe different buffering behaviours of the haemoglobin tetramer. Itiro Tyuma (1984) gives the following brief definition:
- Alkaline Bohr effect: protons are released by haemoglobin when it is oxygenated at physiological pH
- Acid Bohr effect: protons are absorbed by haemoglobin when it is oxygenated at a low pH
This acid Bohr effect is also occasionally referred to as the "reverse Bohr effect", because haemoglobin does the opposite of the thing it is normally supposed to do with protons. The pH value which seems to be the cut-off for this sort of misbehaviour is actually 6.0, which makes the backwardness of the acid Bohr effect seem rather irrelevant (because when would that ever happen). Moreover, these terms appear to have depreciated with the decades, as they no longer crop up in the literature as much as they used to in the seventies and eighties. These days, the "alkaline Bohr effect" is simply called "the Bohr effect," as it describes what normally happens at a physiological pH. The "acid Bohr effect" is less researched, and remains something of a mystery, as there does not appear to be a satisfactory molecular mechanism to explain it.
An acidic environment promotes the formation of a bond between the carboxyl group of histidine 146 and a lysine residue in the α subunit of the other αβ dimer. The ionic bond then places the histidine molecule in a position where its positively charged side chain can participate in a "salt bridge" with a negatively charged aspartate (94) on the same β-subunit. The formation of this bond stabilises the deoxygenated T-state; on the other hand oxyhaemoglobin cannot form this sort of bond and is unaffected by pH. Thus, as soon as oxyhaemoglobin releases its O2 cargo, the presence of a low pH locks it in an unreceptive state, preventing it from binding oxygen molecules.
The formation of this salt bridge is contingent on the "protonation" of the side chain - if there is no positive charge, obviously there can be no interaction. This is where the influence of pH comes in. The presence or absence of a positive charge on this side chain is governed by pH, with a pKa of around 7.0. Thus, at a physiological pH, there is no bond, and at a pH more typical of working muscle (7.20 or so) a greater proportion of deoxyhaemoglobin molecules are stabilised.
Similarly to the effect of pH, but via a different mechanism, CO2 improves the stability of deoxyhaemoglobin. It does so by binding to the terminal amino groups, forming a negatively charged carbamate group. These carbamate groups form at the interface between the αβ dimers. These negative charges then form salt bridge bonds to the positively charged amino groups and side chains, stabilising the molecule in the T-state and favouring the release of oxygen.
In fact, this carbamate formation is a useful method of transporting CO2 back to the lungs, and accounts for 14% or so (or, 10%? 15%?) of total CO2 transport.
The combined influence of CO2 and CO2-associated changes in pH on the shape of the oxygen-haemoglobin dissociation curve can be seen in the original 1904 paper by Bohr Hasselbalch and Krogh:
The influence of CO2 alone, however, is substantially smaller. Changes in pH produced by CO2 dissociation account for much of the above "curvature".