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This study investigated how transient receptor potential cation channel subfamily V member 1 (TRPV1), 1\u2010phosphatidylinositol 4,5\u2010bisphosphate phosphodiesterase gamma\u20101 (PLC\u03b31), and P2X purinoceptor 7 (P2X7) modulate the levels of intracellular calcium ions (Ca<jats:sup>2+<\/jats:sup>) and adenosine triphosphate (ATP) in M\u00fcller cells and retinal ganglion cells (RGCs) under conditions of elevated intraocular pressure (IOP). M\u00fcller cells were maintained at hydrostatic pressure (HP). <jats:italic>TRPV1<\/jats:italic>\u2010 and <jats:italic>PLCG1<\/jats:italic>\u2010silenced M\u00fcller cells and <jats:italic>P2X7<\/jats:italic>\u2010silenced RGCs were constructed by transfection with short interfering RNA (siRNAs). RGCs were cultured with the conditioned media of M\u00fcller cells under HP. A mouse model of chronic ocular hypertension (COH) was established and used to investigate the role of <jats:italic>TRPV1<\/jats:italic> in RGCs <jats:italic>in vivo<\/jats:italic>. M\u00fcller cells and RGCs were analyzed by ATP release assays, intracellular calcium assays, CCK\u20108 assays, EdU (5\u2010ethynyl\u20102\u2032\u2010deoxyuridine) staining, TUNEL staining, flow cytometry, and transmission electron microscopy. <jats:italic>In vivo<\/jats:italic> changes in inner retinal function were evaluated by hematoxylin and eosin (H&amp;E) staining and TUNEL staining. Western blot analyses were performed to measure the levels of related proteins. Our data showed that HP increased the levels of ATP and Ca<jats:sup>2+<\/jats:sup> influx in M\u00fcller cells, and those increases were accompanied by the upregulation of TRPV1 and p\u2010PLC\u03b31 expression. Suppression of <jats:italic>TRPV1<\/jats:italic> or <jats:italic>PLCG1<\/jats:italic> expression in M\u00fcller cells significantly decreased the ATP levels and intracellular Ca<jats:sup>2+<\/jats:sup> accumulation induced by HP. Knockdown of <jats:italic>TRPV1<\/jats:italic>, <jats:italic>PLCG1,<\/jats:italic> or <jats:italic>P2X7<\/jats:italic> significantly decreased apoptosis and autophagy in RGCs cultured in the conditioned media of HP\u2010treated M\u00fcller cells. Moreover, <jats:italic>TRPV1<\/jats:italic> silencing decreased RGC apoptosis and autophagy in the <jats:italic>in vivo<\/jats:italic> model of COH. Collectively, inhibition of TRPV1\/PLC\u03b31 and P2X7 expression may be a useful therapeutic strategy for managing RGC death in glaucoma.<\/jats:p>","DOI":"10.1111\/febs.17075","type":"journal-article","created":{"date-parts":[[2024,2,23]],"date-time":"2024-02-23T09:59:20Z","timestamp":1708682360000},"page":"2703-2714","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["M\u00fcller cells under hydrostatic pressure modulate retinal cell survival via <scp>TRPV1<\/scp>\/<scp>PLC\u03b31<\/scp> complex\u2010mediated calcium influx in experimental glaucoma"],"prefix":"10.1111","volume":"291","author":[{"given":"Huiling","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Cataract, Shenzhen Eye Hospital, Shenzhen Eye Institute Jinan University  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danyao","family":"Nie","sequence":"additional","affiliation":[{"name":"Department 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