If you've ever experienced altitude sickness, you'll know that living at high altitude isn't easy. However, the lower oxygen levels at higher altitudes don't cause problems for everyone, and in the mountain ranges of western North America some species of ground squirrels can live quite happily at elevations of up to 4300 m above sea level. What's more, these small mammals are used to low oxygen levels found in their poorly ventilated burrows during hibernation. So what makes them so resilient to poor oxygen conditions? Angela Fago, from the Aarhus University, Denmark, and Jay F. Storz, from the University of Nebraska, USA, joined forces to find out (p. 4264).Fago and Storz began by assembling a team that travelled from Nebraska to the Rocky Mountains of Colorado and then onto Alaska to collect blood samples from six different species of ground squirrel living at different altitudes ranging from 200 to 4300 m. Back in the lab, Fago's group began their experiments by measuring the effects of two allosteric effectors, 2,3-diphosphoglycerate (DPG) and chloride anions, on the ability of the oxygen-carrying protein haemoglobin to bind oxygen. ‘These small molecules and ions normally bind to the haemoglobin and they tend to decrease the oxygen affinity of the haemoglobin’, explains Fago. ‘This is favourable for species living at sea level, but in species living at high altitude, these co-factors normally don't bind so strongly, so that the haemoglobin remains in a high affinity form.’ In fact, in the case of the ground squirrels, Fago's team found that neither allosteric effector affected oxygen uptake whatsoever.The team then went on to investigate the effect of lowering pH on blood samples from two ground squirrel species inhabiting different altitudes. Fago explains that lowering pH stabilises the haemoglobin in a low-affinity conformation, in what is known as the Bohr effect, and this helps to release oxygen where it is needed in the tissues. Animals living at high altitude often show a bigger Bohr effect to compensate for the fact that their haemoglobin generally already has a higher affinity for oxygen, and indeed both samples were strongly affected by lowering the pH. However, unusually, both the highland inhabitant (2000–4300 m) and the lowland inhabitant (200–2000 m) performed as well as each other and Fago believes that ‘it shows that subterranean life puts a kind of stress on these animals so they are able to withstand different conditions and already had what it takes to be able to colonise high-altitude environments.’Meanwhile, Storz's team focused on analysing the haemoglobin proteins in more detail. Looking at the amino acid residues that are crucial for binding H+ ions and aiding the Bohr effect in human haemoglobin, the team found amino acid substitutions that would in theory reduce, not increase, the Bohr effect. To add to the riddle, Storz's group found that all the amino acids that bind allosteric effectors in human haemoglobin remained unchanged in the ground squirrel's haemoglobin, even though Fago's results suggested that neither DPG nor chloride could bind the haemoglobin to an appreciable extent. It appears that, because of some subtle differences in structure, identical amino acids do not have identical effects in human and ground squirrel haemoglobins. Fago concludes, ‘We still have a lot to learn from doing comparative measurements and although the human haemoglobin is one solution to the problem, it's not the only solution.’
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Nov 1, 2017
A A Nikol’Skii 
Open Access