Neel D. Pasricha , Ethan S. Lindgren , Rongshan Yan , Yien-Ming Kuo , Matilda Chan , Alan S. Verkman , Tifany Chu , Pattareeya Yottasan , Livia de Souza Goncalves , Onur Cil
{"title":"钙感受体（CaSR）调节眼表氯离子转运，抑制钙感受体可促进眼表水合。","authors":"Neel D. Pasricha , Ethan S. Lindgren , Rongshan Yan , Yien-Ming Kuo , Matilda Chan , Alan S. Verkman , Tifany Chu , Pattareeya Yottasan , Livia de Souza Goncalves , Onur Cil","doi":"10.1016/j.jtos.2024.06.002","DOIUrl":null,"url":null,"abstract":"<div><h3>Purpose</h3><p>Ocular surface hydration is critical for eye health and its impairment can lead to dry eye disease. Extracellular calcium-sensing receptor (CaSR) is regulator of ion transport in epithelial cells expressing cystic fibrosis transmembrane conductance regulator (CFTR) Cl<sup>−</sup> channel. CFTR is also a major ion channel in ocular surface epithelia, however the roles of CaSR in ocular surface are not well studied. This study aims to investigate expression and functional roles of CaSR in ocular surface.</p></div><div><h3>Methods</h3><p>CaSR immunostaining was performed in mouse and human cornea and conjunctiva. Ocular surface potential difference (OSPD) and tear fluid volume measurements were performed in mice with topically applied cinacalcet (CaSR activator) and NPS-2143 (CaSR inhibitor).</p></div><div><h3>Results</h3><p>CaSR is expressed in corneal and conjunctival epithelia of mice and humans. Topically administered CaSR activator cinacalcet inhibits cAMP agonist forskolin-induced Cl<sup>−</sup> secretion and CFTR activity up to 90 %. CaSR inhibitor NPS-2143 stimulates CFTR-mediated Cl<sup>−</sup> secretion in mouse ocular surface, after which cAMP agonist forskolin had minimal additional secretory effects. Single dose NPS-2143 treatment (as an eye drop) increases tear fluid volume in mice by ∼60 % compared to vehicle treatment. NPS-2143 effect on tear volume lasts at least 8 h after single dose.</p></div><div><h3>Conclusions</h3><p>CaSR is a key regulator of ocular surface ion transport and CaSR inhibition promotes Cl<sup>−</sup> and tear secretion in the ocular surface. If they are found to be effective in in dry eye models, CaSR inhibitors (currently in clinical development) can potentially be repurposed as novel prosecretory treatments for dry eye disease.</p></div>","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"34 ","pages":"Pages 30-37"},"PeriodicalIF":5.9000,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Calcium-sensing receptor (CaSR) modulates ocular surface chloride transport and its inhibition promotes ocular surface hydration\",\"authors\":\"Neel D. Pasricha , Ethan S. Lindgren , Rongshan Yan , Yien-Ming Kuo , Matilda Chan , Alan S. Verkman , Tifany Chu , Pattareeya Yottasan , Livia de Souza Goncalves , Onur Cil\",\"doi\":\"10.1016/j.jtos.2024.06.002\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Purpose</h3><p>Ocular surface hydration is critical for eye health and its impairment can lead to dry eye disease. Extracellular calcium-sensing receptor (CaSR) is regulator of ion transport in epithelial cells expressing cystic fibrosis transmembrane conductance regulator (CFTR) Cl<sup>−</sup> channel. CFTR is also a major ion channel in ocular surface epithelia, however the roles of CaSR in ocular surface are not well studied. This study aims to investigate expression and functional roles of CaSR in ocular surface.</p></div><div><h3>Methods</h3><p>CaSR immunostaining was performed in mouse and human cornea and conjunctiva. Ocular surface potential difference (OSPD) and tear fluid volume measurements were performed in mice with topically applied cinacalcet (CaSR activator) and NPS-2143 (CaSR inhibitor).</p></div><div><h3>Results</h3><p>CaSR is expressed in corneal and conjunctival epithelia of mice and humans. Topically administered CaSR activator cinacalcet inhibits cAMP agonist forskolin-induced Cl<sup>−</sup> secretion and CFTR activity up to 90 %. CaSR inhibitor NPS-2143 stimulates CFTR-mediated Cl<sup>−</sup> secretion in mouse ocular surface, after which cAMP agonist forskolin had minimal additional secretory effects. Single dose NPS-2143 treatment (as an eye drop) increases tear fluid volume in mice by ∼60 % compared to vehicle treatment. NPS-2143 effect on tear volume lasts at least 8 h after single dose.</p></div><div><h3>Conclusions</h3><p>CaSR is a key regulator of ocular surface ion transport and CaSR inhibition promotes Cl<sup>−</sup> and tear secretion in the ocular surface. If they are found to be effective in in dry eye models, CaSR inhibitors (currently in clinical development) can potentially be repurposed as novel prosecretory treatments for dry eye disease.</p></div>\",\"PeriodicalId\":54691,\"journal\":{\"name\":\"Ocular Surface\",\"volume\":\"34 \",\"pages\":\"Pages 30-37\"},\"PeriodicalIF\":5.9000,\"publicationDate\":\"2024-06-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Ocular Surface\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S154201242400065X\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"OPHTHALMOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Ocular Surface","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S154201242400065X","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"OPHTHALMOLOGY","Score":null,"Total":0}
Calcium-sensing receptor (CaSR) modulates ocular surface chloride transport and its inhibition promotes ocular surface hydration
Purpose
Ocular surface hydration is critical for eye health and its impairment can lead to dry eye disease. Extracellular calcium-sensing receptor (CaSR) is regulator of ion transport in epithelial cells expressing cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel. CFTR is also a major ion channel in ocular surface epithelia, however the roles of CaSR in ocular surface are not well studied. This study aims to investigate expression and functional roles of CaSR in ocular surface.
Methods
CaSR immunostaining was performed in mouse and human cornea and conjunctiva. Ocular surface potential difference (OSPD) and tear fluid volume measurements were performed in mice with topically applied cinacalcet (CaSR activator) and NPS-2143 (CaSR inhibitor).
Results
CaSR is expressed in corneal and conjunctival epithelia of mice and humans. Topically administered CaSR activator cinacalcet inhibits cAMP agonist forskolin-induced Cl− secretion and CFTR activity up to 90 %. CaSR inhibitor NPS-2143 stimulates CFTR-mediated Cl− secretion in mouse ocular surface, after which cAMP agonist forskolin had minimal additional secretory effects. Single dose NPS-2143 treatment (as an eye drop) increases tear fluid volume in mice by ∼60 % compared to vehicle treatment. NPS-2143 effect on tear volume lasts at least 8 h after single dose.
Conclusions
CaSR is a key regulator of ocular surface ion transport and CaSR inhibition promotes Cl− and tear secretion in the ocular surface. If they are found to be effective in in dry eye models, CaSR inhibitors (currently in clinical development) can potentially be repurposed as novel prosecretory treatments for dry eye disease.
期刊介绍：
The Ocular Surface, a quarterly, a peer-reviewed journal, is an authoritative resource that integrates and interprets major findings in diverse fields related to the ocular surface, including ophthalmology, optometry, genetics, molecular biology, pharmacology, immunology, infectious disease, and epidemiology. Its critical review articles cover the most current knowledge on medical and surgical management of ocular surface pathology, new understandings of ocular surface physiology, the meaning of recent discoveries on how the ocular surface responds to injury and disease, and updates on drug and device development. The journal also publishes select original research reports and articles describing cutting-edge techniques and technology in the field.
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