We are encouraged that Cooper, Occhipinti and Boron (Cooper et al. 2015) agree that CO2 passage through membrane proteins (‘gas channels’) should not be considered a universal phenomenon. We draw attention to our recent findings (Hulikova & Swietach, 2014) that membranes in tissue growths of different cellular origin are not rate-limiting for CO2 transport. This indicates that gas channels are not obligatory for CO2 exchange across membranes.
Cooper et al. have proposed a sliding scale of gas channel dependence using examples from several cell types, ranked by cholesterol content (a factor believed to decrease CO2 permeability), but without considering differences in the size of unstirred layers (USLs). Since USLs remain ill defined (Missner & Pohl, 2009), it is not possible to determine whether slow CO2 transport in cholesterol-rich cells is due to slow permeation across the membrane or adjoining USLs. Resistance across USLs cannot be changed by permeation through gas channels, therefore cholesterol content alone is not a robust predictor of gas channel dependence. Without information on USLs, the presumption that ‘low (experimentally measured CO2 permeability) represents (background CO2 permeability of the lipid matrix)’ cannot be made confidently. Moreover, the notion that cholesterol decreases gas diffusivity has been challenged by studies showing no effect of cholesterol on the transversal diffusivity of hydrophobic solutes (Zocher et al. 2013).
In contrast to the controversial effect of cholesterol on CO2 transport, it is beyond doubt that gas flux across the lipid matrix will be reduced substantially in membranes containing a near-confluent array of integral proteins. These integral proteins are also likely to produce a highly tortuous nano-environment on either side of the membrane due to their protrusions. Insertion of aquaporins may provide a route for CO2 passage (i.e. a bona fide channel); alternatively, insertion may loosen the density of impermeable protein protrusions that otherwise obstruct access to the membrane. Under the latter mechanism, aquaporins (and other gas channel candidates) would increase CO2 transport, but without functioning as gas channels. To distinguish these modes of action, a more complete understanding of the juxta-membranous environment is warranted.
In conclusion, an assessment of the role of gas channels in CO2 transport awaits accurate determination of the resistances to CO2 flow imposed by the lipid matrix, unstirred layers (USLs) and membrane proteins. In the meantime, it is important to agree on naming conventions and we make two suggestions. Firstly, measurements of CO2 movement in and out of cells need not represent membrane CO2 permeability () if the rate-limiting barrier is outside the membrane. The absence of CO2 transport across the apical pole of epithelial cells may not solely be due to low . Secondly, since USLs are not part of membranes, the concept of an ‘apparent membrane permeability’ is misleading, and a more general term (e.g. apparent CO2 permeability) is proposed.