Abstract
Breathing 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.
Highlights
Breathing is highly sensitive to the PCO2 of arterial blood
CO2 is detected via the consequent change in pH, and pH is a sufficient stimulus for all adaptive changes in breathing in response to hypercapnia6. pHsensitive K+ channels (TASKs and KIRs) are potential transducers
Systemic injection of a selective GPR4 antagonist modestly reduced the ventilatory response to CO2, but this same antagonist when administered centrally had no effect on the CO2 sensitivity of breathing[20]
Summary
Breathing is highly sensitive to the PCO2 of arterial blood. CO2 is detected via the proxy of pH, CO2 acting directly via Cx26 may contribute to the regulation of breathing. A pH sensitive receptor, GPR4, has been linked to central chemosensitivity in the RTN. A mechanism of pH-dependent release of ATP from ventral medullary glial cells may contribute to the CO2dependent regulation of breathing[21]. The CO2-dependent opening of Cx26 hemichannels can occur in the absence of membrane depolarisation and at physiological levels of extracellular Ca2+ 27–29,33. This direct gating of Cx26 is an important mechanism that underlies CO2-dependent ATP release[26,27,34,35] and provides a potential mechanism for the direct action of CO2 on breathing. The role of direct sensing of CO2 in the regulation of breathing remains uncertain because genetic evidence linking Cx26 to the control of breathing has been lacking, and the cells that could mediate direct CO2 sensing via Cx26 have not been identified
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