Molecular basis of a novel adaptation to hypoxic-hypercapnia in a strictly fossorial mole

Abstract

BackgroundElevated blood O2 affinity enhances survival at low O2 pressures, and is perhaps the best known and most broadly accepted evolutionary adjustment of terrestrial vertebrates to environmental hypoxia. This phenotype arises by increasing the intrinsic O2 affinity of the hemoglobin (Hb) molecule, by decreasing the intracellular concentration of allosteric effectors (e.g., 2,3-diphosphoglycerate; DPG), or by suppressing the sensitivity of Hb to these physiological cofactors.ResultsHere we report that strictly fossorial eastern moles (Scalopus aquaticus) have evolved a low O2 affinity, DPG-insensitive Hb - contrary to expectations for a mammalian species that is adapted to the chronic hypoxia and hypercapnia of subterranean burrow systems. Molecular modelling indicates that this functional shift is principally attributable to a single charge altering amino acid substitution in the β-type δ-globin chain (δ136Gly→Glu) of this species that perturbs electrostatic interactions between the dimer subunits via formation of an intra-chain salt-bridge with δ82Lys. However, this replacement also abolishes key binding sites for the red blood cell effectors Cl-, lactate and DPG (the latter of which is virtually absent from the red cells of this species) at δ82Lys, thereby markedly reducing competition for carbamate formation (CO2 binding) at the δ-chain N-termini.ConclusionsWe propose this Hb phenotype illustrates a novel mechanism for adaptively elevating the CO2 carrying capacity of eastern mole blood during burst tunnelling activities associated with subterranean habitation.

Origin and mechanism of thermal insensitivity in mole hemoglobins: a test of the ‘additional’ chloride binding site hypothesis

“…Later work revealed that Hbs possessing 8Lys and 76Lys together with His or Asn at 77 display numerically reduced ⌬HЈ values in the presence of 0.1moll -1 Cl -relative to human HbA (-41kJmol -1 ); HbA possesses a neutral Ala residue at 76, which presumably prevents Cl -from bridging this positively charged cavity (De Rosa et al, 2004). Notably, and consistent with the 'additional' Cl -binding site hypothesis, the -like -globin chains of coast and eastern mole Hbs have Lys at positions 8 and 76 together with Asn at position 77 (Campbell et al, 2010b).…”

“…Interestingly, the effects of temperature on the whole-blood-O 2 affinity of coast, eastern and star-nosed (Condylura cristata) moles indicated that the blood of the first two species is considerably less sensitive to temperature than that of the latter (Campbell et al, 2010b). This finding is surprising given that the star-nosed mole is not only semi-aquatic, but is distributed substantially farther north than the thermally buffered, strictly fossorial coast and eastern moles (Petersen and Yates, 1980).…”

“…Taken together, these results raise the possibility that a differential ability to bind chloride ions may underlie the observed differences in the whole-blood ⌬HЈ of coast (-1.0kJmol -1 ) and eastern moles (-8.3kJmol -1 ) relative to that of the star-nosed mole (-29.9kJmol -1 ) (Campbell et al, 2010b). We thus hypothesized that the higher thermal sensitivity of star-nosed mole blood may be attributed to residue variations at positions 8, 76 and 77 of the -type chain, creating an unfavourable environment for chloride binding.…”

“…In fact, star-nosed moles have been observed tunnelling in snow and even diving beneath ice during the winter (Merriam, 1884;Hamilton, 1931). Results of Campbell and coworkers (Campbell et al, 2010b) further suggested that coast and eastern mole Hbs possess an extra (relative to human HbA) Cl -binding site that does not overlap with DPG binding. Like that of coast and eastern moles, bovine Hb possesses a specific and 'additional' (with respect to human HbA) oxygenation-linked Cl -binding site (De Rosa et al, 2004).…”

“…We previously determined that the individual Hb components of the coast mole (Scapanus orarius) and the eastern mole (Scalopus aquaticus) likewise possess numerically low enthalpies of oxygenation (between -8 and -14kJmol -1 O 2 ) in the presence of allosteric effectors, a trait that was hypothesized to minimize the impairment of O 2 uptake at the lungs while burrowing in hypoxic tunnels (Campbell et al, 2010b). Interestingly, the effects of temperature on the whole-blood-O 2 affinity of coast, eastern and star-nosed (Condylura cristata) moles indicated that the blood of the first two species is considerably less sensitive to temperature than that of the latter (Campbell et al, 2010b).…”