Mechanosensitive release of adenosine 5′‐triphosphate through pannexin channels and mechanosensitive upregulation of pannexin channels in optic nerve head astrocytes: A mechanism for purinergic involvement in chronic strain. Issue 9 (19th May 2014)

• Record Type: Journal Article
• Authors: Beckel, Jonathan M.; Argall, Arthur J.; Lim, Jason C.; Xia, Jingsheng; Lu, Wennan; Coffey, Erin E.; Macarak, Edward J.; Shahidullah, Mohammed; Delamere, Nicholas A.; Zode, Gulab S.; Sheffield, Val C.; Shestopalov, Valery I.; Laties, Alan M.; Mitchell, Claire H.
• Is Part Of: Glia. Volume 62:Issue 9(2014:Sep.)
• Page Start: 1486
• Page End: 1501
• Publication Date: 2014-05-19
• Subjects: Neuroglia -- Periodicals; Neurology -- Periodicals; 611.0188
• DOI: 10.1002/glia.22695
• Languages: English
• ISSNs: 0894-1491

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>As adenosine 5′‐triphosphate (ATP) released from astrocytes can modulate many neural signaling systems, the triggers and pathways for this ATP release are important. Here, the ability of mechanical strain to trigger ATP release through pannexin channels and the effects of sustained strain on pannexin expression were examined in rat optic nerve head astrocytes. Astrocytes released ATP when subjected to 5% of equibiaxial strain or to hypotonic swelling. Although astrocytes expressed mRNA for pannexins 1–3, connexin 43, and VNUT, pharmacological analysis suggested a predominant role for pannexins in mechanosensitive ATP release, with Rho kinase contribution. Astrocytes from <italic>panx1<sup>−/−</sup></italic> mice had reduced baseline and stimulated levels of extracellular ATP, confirming the role for pannexins. Swelling astrocytes triggered a regulatory volume decrease that was inhibited by apyrase or probenecid. The swelling‐induced rise in calcium was inhibited by P2X7 receptor antagonists A438079 and AZ10606120, in addition to apyrase and carbenoxolone. Extended stretch of astrocytes <italic>in vitro</italic> upregulated expression of <italic>panx1</italic> and <italic>panx2</italic> mRNA. A similar upregulation was observed <italic>in vivo</italic> in optic nerve head tissue from the <italic>Tg‐MYOC<sup>Y437H</sup></italic> mouse model of chronic glaucoma; genes for <italic>panx1</italic>, <italic>panx2</italic>, and <italic>panx3</italic> were increased, whereas immunohistochemistry confirmed increased expression of pannexin 1 protein. In summary, astrocytes released ATP in response to mechanical strain, with pannexin 1 the predominant efflux pathway. Sustained strain upregulated pannexins <italic>in vitro</italic> and <italic>in vivo</italic>. Together, these findings provide a mechanism by which extracellular ATP remains elevated under chronic mechanical strain, as found in the optic nerve head of patients with glaucoma. GLIA 2014;62:1486–1501</p> </abstract>