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Connexin hemichannel-mediated CO2-dependent release of ATP in the medulla oblongata contributes to central respiratory chemosensitivity
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Huckstepp, Robert T. R., Bihi, Rachid Id, Eason, Robert, Spyer, K. Michael, Dicke, Nikolai, Willecke, Klaus, Marina, Nephtali, Gourine, Alexander V. and Dale, Nicholas. (2010) Connexin hemichannel-mediated CO2-dependent release of ATP in the medulla oblongata contributes to central respiratory chemosensitivity. Journal of Physiology, Vol.588 (No.20). pp. 3901-3920. ISSN 0022-3751
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Official URL: http://dx.doi.org/10.1113/jphysiol.2010.192088
Abstract
Arterial P-CO2, a major determinant of breathing, is detected by chemosensors located in the brainstem. These are important for maintaining physiological levels of CO2 in the blood and brain, yet the mechanisms by which the brain senses CO2 remain controversial. As ATP release at the ventral surface of the brainstem has been causally linked to the adaptive changes in ventilation in response to hypercapnia, we have studied the mechanisms of CO2-dependent ATP release in slices containing the ventral surface of the medulla oblongata. We found that CO2-dependent ATP release occurs in the absence of extracellular acidification and correlates directly with the level of P-CO2. ATP release is independent of extracellular Ca2+ and may occur via the opening of a gap junction hemichannel. As agents that act on connexin channels block this release, but compounds selective for pannexin-1 have no effect, we conclude that a connexin hemichannel is involved in CO2-dependent ATP release. We have used molecular, genetic and immunocytochemical techniques to demonstrate that in the medulla oblongata connexin 26 (Cx26) is preferentially expressed near the ventral surface. The leptomeninges, subpial astrocytes and astrocytes ensheathing penetrating blood vessels at the ventral surface of the medulla can be loaded with dye in a CO2-dependent manner, suggesting that gating of a hemichannel is involved in ATP release. This distribution of CO2-dependent dye loading closely mirrors that of Cx26 expression and colocalizes to glial fibrillary acidic protein (GFAP)-positive cells. In vivo, blockers with selectivity for Cx26 reduce hypercapnia-evoked ATP release and the consequent adaptive enhancement of breathing. We therefore propose that Cx26-mediated release of ATP in response to changes in P-CO2 is an important mechanism contributing to central respiratory chemosensitivity.
| Item Type: | Journal Article | ||||
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| Subjects: | R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry Q Science > QP Physiology |
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| Divisions: | Faculty of Science > Life Sciences (2010- ) > Biological Sciences ( -2010) | ||||
| Journal or Publication Title: | Journal of Physiology | ||||
| Publisher: | Wiley-Blackwell Publishing Ltd. | ||||
| ISSN: | 0022-3751 | ||||
| Official Date: | 15 October 2010 | ||||
| Dates: |
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| Volume: | Vol.588 | ||||
| Number: | No.20 | ||||
| Number of Pages: | 20 | ||||
| Page Range: | pp. 3901-3920 | ||||
| Identification Number: | 10.1113/jphysiol.2010.192088 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access | ||||
| Funder: | German Research Association, Juergen Manchot Foundation | ||||
| Grant number: | SFB 645, B2 | ||||
| URI: | http://wrap.warwick.ac.uk/id/eprint/4969 |
Data sourced from Thomson Reuters' Web of Knowledge
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