Breathing molecule discovered

Vital to treating respiratory conditions — which could now be better targeted and treated — is the discovery of a vital molecule that regulates breathing. Discovered at the University of Warwick, UK.

Professor Nicholas Dale at the School of Life Sciences, University of Warwick, Coventry, UK, has identified Connexin26 (Cx26) as a key molecule that reacts to CO2 in our bodies to activate breathing.

Cx26 molecules detect levels of CO2 in our blood-stream, and when levels reach a certain point, trigger the excretion of CO2 to bind to hemichannels of Cx26 causing them to open and allow release of the neurotransmitter ATP - creating blood flow to our brain.

Without this essential molecular function, harmful levels of CO2 would remain in the bloodstream, making breathing difficult or impossible.

Mutations in Cx26 are directly connected to a number of serious conditions - ranging from congenital deafness, respiratory disorders, and serious syndromes that affect our skin, to vision and hearing. As Cx26 is vital to breathing, people carrying mutations may be at risk for sleep apnea.

This is because hemichannels are composed of two connexons and are a specialized intercellular connection between a multitude of animal cell-types. They directly connect the cytoplasm of two cells, and allow various molecules, ions and electrical impulses to directly pass through a regulated gate between cells. They are also called gap junctions.

One gap junction channel is composed of two connexons (or hemichannels),  made of two connexons connected across an intercellular space. Gap junctions are analogous to the plasmodesmata that join plant cells.

Gap junctions occur in virtually all tissues of the body, with the exception of adult fully developed skeletal muscle and mobile cell types such as sperm or red blood cells. Gap junctions, however, are not found in simpler organisms such as sponges and slime molds.

Identifying mutations and working out how to restore Cx26 to its normal function could lead to effective, targeted personalised treatments to mitigate risks and improve quality of life.

Different animals have varying levels of sensitivity to CO2. Professor Dale's group used this knowledge to examine whether properties of Cx26 matched physiological requirements of birds that fly at high-altitude yet tolerate low levels of CO2; humans and rats, which are broadly similar in respitory needs at an intermediate level; and mole rats that live exclusively underground while tolerating very high levels of CO2.

They found that CO2 binding properties have matched sensitivities in these different animals. Evolutionary natural selection has thus modified the CO2-binding properties of Cx26 - showing this molecule is a universally important sensor of CO2 in warm blooded animals.

"Important molecules with universal physiological functions are shaped by evolution.

"We have exploited this simple fact to show how CO2-binding characteristics of Cx26 are important in our bodies too. This is likely to open up new ways to identify and treat people at risk of sleep apneas."

Nicholas Dale PhD, Professor, School of Life Sciences, University of Warwick, Coventry, UK

The research, 'Evolutionary adaptation of the sensitivity of Connexin26 hemichannels to CO2', is published in the Proceedings of the Royal Society B.

Abstract
CO2 readily combines with H2O to form Embedded Image and H+. Because an increase of only 100 nM in the concentration of H+ (a decrease of 0.1 unit of pH) in blood can prove fatal, the regulated excretion of CO2 during breathing is an essential life-preserving process. In rodents and humans, this vital process is mediated in part via the direct sensing of CO2 via connexin26 (Cx26). CO2 binds to hemichannels of Cx26 causing them to open and allow release of the neurotransmitter ATP. If Cx26 were to be a universal and important CO2 sensor across all homeothermic animals, then a simple hypothesis would posit that it should exhibit evolutionary adaptation in animals with different homeostatic set points for the regulation of partial pressure of arterial CO2 (PaCO2). In humans and rats, PaCO2 is regulated around a set point of 40 mmHg. By contrast, birds are able to maintain cerebral blood flow and breathing at much lower levels of PaCO2. Fossorial mammals, such as the mole rat, live exclusively underground in burrows that are both hypoxic and hypercapnic and can thrive under very hypercapnic conditions. We have therefore compared the CO2 sensitivity of Cx26 from human, chicken, rat and mole rat (Heterocephalus glaber). We find that both the affinity and cooperativity of CO2 binding to Cx26 have been subjected to evolutionary adaption in a manner consistent with the homeostatic requirements of these four species. This is analogous to the evolutionary adaptation of haemoglobin to the needs of O2 transport across the animal kingdom and supports the hypothesis that Cx26 is an important and universal CO2 sensor in homeotherms.
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Diagram showing Cx26 molecule reacting with carbon dioxide,
to trigger breathing and increase blood-flow.
Image Credit: University of Warwick