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

Jonathan M Beckel; Arthur J Argall; Jason C Lim; Jingsheng Xia; Wennan Lu; Erin E Coffey; Edward J Macarak; Mohammed Shahidullah; Nicholas A Delamere; Gulab S Zode; Val C Sheffield; Valery I Shestopalov; Alan M Laties; Claire H Mitchell

doi:10.1002/glia.22695

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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

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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

Jonathan M Beckel, Arthur J Argall, Jason C Lim, Jingsheng Xia, Wennan Lu, Erin E Coffey, Edward J Macarak, Mohammed Shahidullah, Nicholas A Delamere, Gulab S Zode, …

Glia, Vol.62(9), pp.1486-1501

09/2014

DOI: 10.1002/glia.22695

PMCID: PMC4133947

PMID: 24839011

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Abstract

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 panx1(-/-) 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 in vitro upregulated expression of panx1 and panx2 mRNA. A similar upregulation was observed in vivo in optic nerve head tissue from the Tg-MYOC(Y437H) mouse model of chronic glaucoma; genes for panx1, panx2, and panx3 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 in vitro and in vivo. 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.

Cytoskeletal Proteins - genetics

Rats, Long-Evans

Glycoproteins - metabolism

Stress, Mechanical

Male

Purinergic P2X Receptor Antagonists - pharmacology

Adenosine Triphosphate - metabolism

Cytoskeletal Proteins - metabolism

Female

Eye Proteins - genetics

Optic Disk - physiology

Glaucoma - physiopathology

Osmotic Pressure - physiology

Disease Models, Animal

Glycoproteins - genetics

Astrocytes - drug effects

Mice, Inbred C57BL

Cells, Cultured

Connexins - genetics

Mice, Transgenic

Nerve Tissue Proteins - genetics

Nucleotide Transport Proteins - metabolism

Connexins - metabolism

Mice, Knockout

Nerve Tissue Proteins - metabolism

Astrocytes - physiology

Animals

Eye Proteins - metabolism

Optic Disk - drug effects

Details

Title: Subtitle: 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
Creators: Jonathan M Beckel - Department of Anatomy and Cell Biology, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Arthur J Argall
Jason C Lim
Jingsheng Xia
Wennan Lu
Erin E Coffey
Edward J Macarak
Mohammed Shahidullah
Nicholas A Delamere
Gulab S Zode
Val C Sheffield
Valery I Shestopalov
Alan M Laties
Claire H Mitchell
Resource Type: Journal article
Publication Details: Glia, Vol.62(9), pp.1486-1501
DOI: 10.1002/glia.22695
PMID: 24839011
PMCID: PMC4133947
NLM abbreviation: Glia
ISSN: 0894-1491
eISSN: 1098-1136
Publisher: United States
Grant note: EY013434 / NEI NIH HHS EY10564 / NEI NIH HHS EY06915 / NEI NIH HHS T32 GM075770 / NIGMS NIH HHS K99 EY022077 / NEI NIH HHS P30 EY001583 / NEI NIH HHS EY09532 / NEI NIH HHS R01 DK069898 / NIDDK NIH HHS EY001583 / NEI NIH HHS R01 EY015537 / NEI NIH HHS GM075770 / NIGMS NIH HHS F32 EY006915 / NEI NIH HHS R01 EY024259 / NEI NIH HHS R01 EY013434 / NEI NIH HHS R01 EY021517 / NEI NIH HHS R01 EY009532 / NEI NIH HHS R01 EY011298 / NEI NIH HHS R24 EY017045 / NEI NIH HHS R00 EY022077 / NEI NIH HHS EY021517 / NEI NIH HHS EY017045 / NEI NIH HHS EY015537 / NEI NIH HHS R01 EY006915 / NEI NIH HHS DK069898 / NIDDK NIH HHS R01 EY010564 / NEI NIH HHS
Language: English
Date published: 09/2014
Academic Unit: Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Ophthalmology and Visual Sciences
Record Identifier: 9984065487302771

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