{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T05:59:52Z","timestamp":1783490392543,"version":"3.55.0"},"reference-count":36,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,6,28]],"date-time":"2021-06-28T00:00:00Z","timestamp":1624838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001818","name":"Research to Prevent Blindness","doi-asserted-by":"publisher","award":["Stein Innovation Award"],"award-info":[{"award-number":["Stein Innovation Award"]}],"id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["EY"],"award-info":[{"award-number":["EY"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>By providing ~70% of the eye\u2019s refractive power, the preocular tear film is essential for optimal vision. However, its integrity is often jeopardized by environmental and pathologic conditions that accelerate evaporation and cause sight-impairing dry eye. A key adaptive response to evaporation-induced tear film hyperosmolarity is the reflex-triggered release of tear-stabilizing mucin from conjunctival goblet cells. Here, we review progress in elucidating the roles of ion channels in mediating this important exocytotic response. Much is now known about the modulatory impact of ATP-sensitive potassium channels, nonspecific cation channels and voltage-gated calcium channels. Recently, we discovered that during unremitting extracellular hyperosmolarity, P2X7 receptor\/channels also become activated and markedly impair goblet cell viability. However, our understanding of possible adaptive benefits of this P2X7 activation remains limited. In the present study, we utilized high-temporal resolution membrane capacitance measurements to monitor the exocytotic activity of single goblet cells located in freshly excised rat conjunctiva. We now report that activation of P2X7 purinoceptors boosts neural-evoked exocytosis and accelerates replenishment of mucin-filled granules after exocytotic depletion. Thus, P2X7 activation exerts a yin-yang effect on conjunctival goblet cells: the high-gain benefit of enhancing the supply of tear-stabilizing mucin is implemented at the high-risk of endangering goblet cell survival.<\/jats:p>","DOI":"10.3390\/ijms22136935","type":"journal-article","created":{"date-parts":[[2021,6,28]],"date-time":"2021-06-28T11:45:40Z","timestamp":1624880740000},"page":"6935","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Impact of P2X7 Purinoceptors on Goblet Cell Function: Implications for Dry Eye"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3221-3011","authenticated-orcid":false,"given":"Donald G.","family":"Puro","sequence":"first","affiliation":[{"name":"Departments of Ophthalmology & Visual Sciences and Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.exer.2003.10.012","article-title":"Contribution of the ocular surface to visual optics","volume":"78","author":"Courville","year":"2004","journal-title":"Exp. Eye Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.jtos.2017.03.006","article-title":"TFOS DEWS II Tear Film Report","volume":"15","author":"Willcox","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2212","DOI":"10.1056\/NEJMra1407936","article-title":"Dry Eye","volume":"378","author":"Clayton","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.jtos.2017.05.011","article-title":"TFOS DEWS II pathophysiology report","volume":"15","author":"Bron","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/S1350-9462(02)00038-1","article-title":"Regulation of mucin and fluid secretion by conjunctival epithelial cells","volume":"21","author":"Dartt","year":"2002","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1038\/mi.2015.53","article-title":"Interaction of IFN-gamma with cholinergic agonists to modulate rat and human goblet cell function","volume":"9","author":"Hodges","year":"2016","journal-title":"Mucosal. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.exer.2012.08.010","article-title":"Signaling pathways used by EGF to stimulate conjunctival goblet cell secretion","volume":"103","author":"Hodges","year":"2012","journal-title":"Exp. Eye Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2872","DOI":"10.1167\/iovs.12-11264","article-title":"Effect of VIP on intracellular [Ca2+], extracellular regulated kinase 1\/2, and secretion in cultured rat conjunctival goblet cells","volume":"54","author":"Li","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"C236","DOI":"10.1152\/ajpcell.00077.2018","article-title":"Role of ion channels in the functional response of conjunctival goblet cells to dry eye","volume":"315","author":"Puro","year":"2018","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"C1305","DOI":"10.1152\/ajpcell.00086.2020","article-title":"How goblet cells respond to dry eye: Adaptive and pathological roles of voltage-gated calcium channels and P2X7 purinoceptors","volume":"318","author":"Puro","year":"2020","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Puro, D.G. (2020). Bioelectric responses of conjunctival goblet cells to dry eye: Impact of ion channels on exocytotic function and viability. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249415"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5661","DOI":"10.1167\/iovs.13-12473","article-title":"Role of PKCalpha activation of Src, PI-3K\/AKT, and ERK in EGF-stimulated proliferation of rat and human conjunctival goblet cells","volume":"54","author":"Li","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/s11302-017-9556-5","article-title":"Hyperosmotic stress induces ATP release and changes in P2X7 receptor levels in human corneal and conjunctival epithelial cells","volume":"13","author":"Pintor","year":"2017","journal-title":"Purinergic Signal."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"McGilligan, V.E., Gregory-Ksander, M.S., Li, D., Moore, J.E., Hodges, R.R., Gilmore, M.S., Moore, T.C., and Dartt, D.A. (2013). Staphylococcus aureus activates the NLRP3 inflammasome in human and rat conjunctival goblet cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0074010"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1016\/j.ajpath.2016.02.004","article-title":"Interferon-gamma-induced unfolded protein response in conjunctival goblet cells as a cause of mucin deficiency in sjogren syndrome","volume":"186","author":"Coursey","year":"2016","journal-title":"Am. J. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1016\/j.ophtha.2017.07.010","article-title":"The pathophysiology of dry eye disease: What we know and future directions for research","volume":"124","author":"Pflugfelder","year":"2017","journal-title":"Ophthalmology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6279","DOI":"10.1167\/iovs.10-7081","article-title":"Interferon-gamma exacerbates dry eye-induced apoptosis in conjunctiva through dual apoptotic pathways","volume":"52","author":"Zhang","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.exer.2013.11.011","article-title":"Topical interferon-gamma neutralization prevents conjunctival goblet cell loss in experimental murine dry eye","volume":"118","author":"Zhang","year":"2014","journal-title":"Exp. Eye Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7545","DOI":"10.1167\/iovs.15-17627","article-title":"Aqueous tear deficiency increases conjunctival interferon-gamma (IFN-gamma) expression and goblet cell loss","volume":"56","author":"Pflugfelder","year":"2015","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1001\/archopht.1984.01040030851031","article-title":"Conjunctival goblet cell densities in ocular surface disease","volume":"102","author":"Nelson","year":"1984","journal-title":"Arch. Ophthalmol."},{"key":"ref_21","first-page":"240","article-title":"Dry eye: An inflammatory ocular disease","volume":"9","author":"Hessen","year":"2014","journal-title":"J. Ophthalmic Vis. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1146\/annurev.pharmtox.40.1.563","article-title":"Pharmacology of cloned P2X receptors","volume":"40","author":"North","year":"2000","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1038\/nprot.2013.069","article-title":"High-resolution membrane capacitance measurements for the study of exocytosis and endocytosis","volume":"8","author":"Rituper","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6174","DOI":"10.1167\/iovs.10-7022","article-title":"Effect of tear hyperosmolarity and signs of clinical ocular surface pathology upon conjunctival goblet cell function in the human ocular surface","volume":"52","author":"Moore","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"108115","DOI":"10.1016\/j.exer.2020.108115","article-title":"Biological functions of tear film","volume":"197","author":"Pflugfelder","year":"2020","journal-title":"Exp. Eye Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.preteyeres.2016.04.005","article-title":"Goblet cells of the conjunctiva: A review of recent findings","volume":"54","author":"Gipson","year":"2016","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2535","DOI":"10.1167\/iovs.02-1117","article-title":"Activation of mitogen-activated protein kinase by cholinergic agonists and EGF in human compared with rat cultured conjunctival goblet cells","volume":"44","author":"Horikawa","year":"2003","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_28","first-page":"531","article-title":"Unusual structure of rat conjunctival epithelium. Light and electron microscopy","volume":"28","author":"Setzer","year":"1987","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1006\/exer.1997.0351","article-title":"Visualization of conjunctival goblet cell actin cytoskeleton and mucin content in tissue whole mounts","volume":"65","author":"Gipson","year":"1997","journal-title":"Exp. Eye Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1038\/380531a0","article-title":"Simultaneous independent measurement of endocytosis and exocytosis","volume":"380","author":"Smith","year":"1996","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.exer.2013.07.013","article-title":"Contact lens interactions with the tear film","volume":"117","author":"Mann","year":"2013","journal-title":"Exp. Eye Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"68","DOI":"10.5935\/0034-7280.20150016","article-title":"Lacrimal osmolarity and ocular surface in experimental model of dry eye caused by toxicity","volume":"74","author":"Marques","year":"2015","journal-title":"Rev. Bras. Oftalmol."},{"key":"ref_33","first-page":"222","article-title":"Electrolyte composition of lacrimal gland fluid and tears of normal and vitamin A-deficient rabbits","volume":"15","author":"Rismondo","year":"1989","journal-title":"CLAO J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1111\/vop.12798","article-title":"Osmolarity of basal and reflex tears of normal dogs","volume":"23","author":"Lamkin","year":"2020","journal-title":"Vet. Ophthalmol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/BF00582306","article-title":"Patch-clamp techniques for time-resolved capacitance measurements in single cells","volume":"411","author":"Lindau","year":"1988","journal-title":"Pflug. Arch."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1007\/s004249900173","article-title":"Admittance-based measurement of membrane capacitance using the EPC-9 patch-clamp amplifier","volume":"439","author":"Gillis","year":"2000","journal-title":"Pflug. Arch."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/6935\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:25:40Z","timestamp":1760163940000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/6935"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,28]]},"references-count":36,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ijms22136935"],"URL":"https:\/\/doi.org\/10.3390\/ijms22136935","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,28]]}}}