Dataset Information

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

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 (Cx26^DN) that removes the CO₂-sensitivity from endogenously expressed wild type Cx26. Expression of Cx26^DN 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.

SUBMITTER: van de Wiel J

PROVIDER: S-EPMC7505967 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

van de Wiel Joseph J Meigh Louise L Bhandare Amol A Cook Jonathan J Nijjar Sarbjit S Huckstepp Robert R Dale Nicholas N

Communications biology 20200921 1

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 cell ...[more]

PMID: 32958814

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Project description:Background and purposeWhile brain MR imaging is routinely performed, the MR imaging assessment of spinal cord pathology in multiple sclerosis (MS) is less frequent in clinical practice. The purpose of this study was to determine whether measurements of medulla oblongata volume (MOV) on routine brain MR imaging could serve as a biomarker of spinal cord damage and disability in MS.Materials and methodsWe identified 45 patients with MS with both head and cervical spinal cord MR imaging and 29 age-matched and sex-matched healthy control subjects with head MR imaging. Disability was assessed by the expanded disability status scale (EDSS) and ambulation index (AI). MOV and upper cervical cord volume (UCCV) were manually segmented; semiautomated segmentation was used for brain parenchymal fraction (BPF). These measures were compared between groups, and linear regression models were built to predict disability.ResultsIn the patients, MOV correlated significantly with UCCV (r = 0.67), BPF (r = 0.45), disease duration (r = -0.64), age (r = -0.47), EDSS score (r = -0.49) and AI (r = -0.52). Volume loss of the medulla oblongata was -0.008 cm(3)/year of age in patients with MS, but no significant linear relationship with age was found for healthy control subjects. The patients had a smaller MOV (mean +/- SD, 1.02 +/- 0.17 cm(3)) than healthy control subjects (1.15 +/- 0.15 cm(3)), though BPF was unable to distinguish between these 2 groups. MOV was smaller in patients with progressive MS (secondary- progressive MS, 0.88 +/- 0.19 cm(3) and primary-progressive MS, 0.95 +/- 0.30 cm(3)) than in patients with relapsing-remitting MS (1.08 +/- 0.15 cm(3)). A model including both MOV and BPF better predicted AI than BPF alone (P = .04). Good reproducibility in MOV measurements was demonstrated for intrarater (intraclass correlation coefficient, 0.97), interrater (0.79), and scan rescan data (0.81).ConclusionMOV is associated with disability in MS and can serve as a biomarker of spinal cord damage.

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

Publications

Connexin26 mediates CO<sub>2</sub>-dependent regulation of breathing via glial cells of the medulla oblongata.

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