CO
            2
            sensing by connexin26 and its role in the control of breathing

Breathing is essential to provide the O 2 required for metabolism and to remove its inevitable CO 2 by-product. The rate and depth of breathing is controlled to regulate the excretion of CO 2 to maintain the pH of arterial blood at physiological values. A widespread consensus is that chemosensory cells in the carotid body and brainstem measure blood and tissue pH and adjust the rate of breathing to ensure its homeostatic regulation. In this review, I shall consider the evidence that underlies this consensus and highlight historical data indicating that direct sensing of CO 2 also plays a significant role in the regulation of breathing. I shall then review work from my laboratory that provides a molecular mechanism for the direct detection of CO 2 via the gap junction protein connexin26 (Cx26) and demonstrates the contribution of this mechanism to the chemosensory regulation of breathing. As there are many pathological mutations of Cx26 in humans, I shall discuss which of these alter the CO 2 sensitivity of Cx26 and the extent to which these mutations could affect human breathing. I finish by discussing the evolution of the CO 2 sensitivity of Cx26 and its link to the evolution of amniotes.

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Connexin26 mediates CO2-dependent regulation of breathing via glial cells of the medulla oblongata

Communications Biology ◽

10.1038/s42003-020-01248-x ◽

2020 ◽

Vol 3 (1) ◽

Cited By ~ 3

Author(s):

Joseph van de Wiel ◽

Louise Meigh ◽

Amol Bhandare ◽

Jonathan Cook ◽

Sarbjit Nijjar ◽

...

Keyword(s):

Glial Cells ◽

Minute Ventilation ◽

Dominant Negative ◽

Structural Motif ◽

Wild Type ◽

Arterial Blood ◽

Highly Sensitive ◽

Fundamental Process ◽

Regulation Of Breathing ◽

Direct Sensing

AbstractBreathing is highly sensitive to the PCO2 of arterial blood. Although CO2 is detected via the proxy of pH, CO2 acting directly via Cx26 may also contribute to the regulation of breathing. Here we exploit our knowledge of the structural motif of CO2-binding to Cx26 to devise a dominant negative subunit (Cx26DN) that removes the CO2-sensitivity from endogenously expressed wild type Cx26. Expression of Cx26DN in glial cells of a circumscribed region of the mouse medulla - the caudal parapyramidal area – reduced the adaptive change in tidal volume and minute ventilation by approximately 30% at 6% inspired CO2. As central chemosensors mediate about 70% of the total response to hypercapnia, CO2-sensing via Cx26 in the caudal parapyramidal area contributed about 45% of the centrally-mediated ventilatory response to CO2. Our data unequivocally link the direct sensing of CO2 to the chemosensory control of breathing and demonstrates that CO2-binding to Cx26 is a key transduction step in this fundamental process.

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Connexin26 mediates CO2-dependent regulation of breathing via glial cells of the medulla oblongata

10.1101/2020.04.16.042440 ◽

2020 ◽

Cited By ~ 2

Author(s):

Joseph Van de Wiel ◽

Louise Meigh ◽

Amol Bhandare ◽

Jonathan Cook ◽

Sarbjit Nijjar ◽

...

Keyword(s):

Glial Cells ◽

Minute Ventilation ◽

Dominant Negative ◽

Structural Motif ◽

Wild Type ◽

Arterial Blood ◽

Highly Sensitive ◽

Fundamental Process ◽

Regulation Of Breathing ◽

Direct Sensing

AbstractBreathing is highly sensitive to the PCO2 of arterial blood. Although CO2 is detected via the proxy of pH, CO2 acting directly via Cx26 may also contribute to the regulation of breathing. Here we exploit our knowledge of the structural motif of CO2-binding to Cx26 to devise a dominant negative subunit (Cx26DN) that removes the CO2-sensitivity from endogenously expressed wild type Cx26. Expression of Cx26DN in glial cells of a circumscribed region of the medulla - the caudal parapyramidal area – reduced the adaptive change in tidal volume and minute ventilation by approximately 30% at 6% inspired CO2. As central chemosensors mediate about 70% of the total response to hypercapnia, CO2-sensing via Cx26 in the caudal parapyramidal area contributed about 45% of the centrally-mediated ventilatory response to CO2. Our data unequivocally links the direct sensing of CO2 to the chemosensory control of breathing and demonstrates that CO2-binding to Cx26 is a key transduction step in this fundamental process.

Download Full-text