{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:48:08Z","timestamp":1792172888196,"version":"4.4.0"},"reference-count":52,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK109887"],"award-info":[{"award-number":["DK109887"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK123610"],"award-info":[{"award-number":["DK123610"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["P30DK090868"],"award-info":[{"award-number":["P30DK090868"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Mutations of\n                      <jats:italic toggle=\"yes\">PKD2<\/jats:italic>\n                      , which encodes polycystin-2, cause autosomal dominant polycystic kidney disease (ADPKD). The prevailing view is that defects in polycystin-2\u2013mediated calcium ion influx in the primary cilia play a central role in the pathogenesis of cyst growth. However, polycystin-2 is predominantly expressed in the endoplasmic reticulum (ER) and more permeable to potassium ions than to calcium ions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The trimeric intracellular cation (TRIC) channel TRIC-B is an ER-resident potassium channel that mediates potassium\u2013calcium counterion exchange for inositol trisphosphate\u2013mediated calcium ion release. Using TRIC-B as a tool, we examined the function of ER-localized polycystin-2 and its role in ADPKD pathogenesis in cultured cells, zebrafish, and mouse models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Agonist-induced ER calcium ion release was defective in cells lacking polycystin-2 and reversed by exogenous expression of TRIC-B.\n                      <jats:italic toggle=\"yes\">Vice versa<\/jats:italic>\n                      , exogenous polycystin-2 reversed an ER calcium-release defect in cells lacking TRIC-B. In a zebrafish model, expression of wild-type but not nonfunctional TRIC-B suppressed polycystin-2\u2013deficient phenotypes. Similarly, these phenotypes were suppressed by targeting the ROMK potassium channel (normally expressed on the cell surface) to the ER. In cultured cells and polycystin-2\u2013deficient zebrafish phenotypes, polycystin-2 remained capable of reversing the ER calcium release defect even when it was not present in the cilia. Transgenic expression of\n                      <jats:italic toggle=\"yes\">Tric-b<\/jats:italic>\n                      ameliorated cystogenesis in the kidneys of conditional\n                      <jats:italic toggle=\"yes\">Pkd2<\/jats:italic>\n                      -inactivated mice, whereas\n                      <jats:italic toggle=\"yes\">Tric-b<\/jats:italic>\n                      deletion enhanced cystogenesis in\n                      <jats:italic toggle=\"yes\">Pkd2<\/jats:italic>\n                      -heterozygous kidneys.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Polycystin-2 in the ER appears to be critical for anticystogenesis and likely functions as a potassium ion channel to facilitate potassium\u2013calcium counterion exchange for inositol trisphosphate\u2013mediated calcium release. The results advance the understanding of ADPKD pathogenesis and provides proof of principle for pharmacotherapy by TRIC-B activators.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.2022010053","type":"journal-article","created":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T10:10:14Z","timestamp":1657793414000},"page":"1501-1516","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":40,"title":["Channel Function of Polycystin-2 in the Endoplasmic Reticulum Protects against Autosomal Dominant Polycystic Kidney Disease"],"prefix":"10.1681","volume":"33","author":[{"given":"Biswajit","family":"Padhy","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Xie","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runping","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, Iowa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9963-3040","authenticated-orcid":false,"given":"Chou-Long","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2022,8]]},"reference":[{"key":"B1-20250823","doi-asserted-by":"crossref","first-page":"2384","DOI":"10.1097\/01.ASN.0000028643.17901.42","article-title":"Genetics and pathogenesis of polycystic kidney disease","volume":"13","author":"Igarashi","year":"2002","journal-title":"J Am Soc Nephrol"},{"key":"B2-20250823","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1146\/annurev.med.60.101707.125712","article-title":"Polycystic kidney disease","volume":"60","author":"Harris","year":"2009","journal-title":"Annu Rev Med"},{"key":"B3-20250823","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1681\/ASN.2017050483","article-title":"Genetic complexity of autosomal dominant polycystic kidney and liver diseases","volume":"29","author":"Cornec-Le Gall","year":"2018","journal-title":"J Am Soc Nephrol"},{"key":"B4-20250823","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/S1097-2765(00)80135-5","article-title":"Somatic mutation in individual liver cysts supports a two-hit model of cystogenesis in autosomal dominant polycystic kidney disease","volume":"2","author":"Watnick","year":"1998","journal-title":"Mol Cell"},{"key":"B5-20250823","doi-asserted-by":"crossref","first-page":"4257","DOI":"10.1172\/JCI64313","article-title":"Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity","volume":"122","author":"Hopp","year":"2012","journal-title":"J Clin Invest"},{"key":"B6-20250823","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/j.cell.2016.09.048","article-title":"The structure of the polycystic kidney disease channel PKD2 in lipid nanodiscs","volume":"167","author":"Shen","year":"2016","journal-title":"Cell"},{"key":"B7-20250823","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1038\/nsmb.3343","article-title":"Structure of the polycystic kidney disease TRP channel polycystin-2 (PC2)","volume":"24","author":"Grieben","year":"2017","journal-title":"Nat Struct Mol Biol"},{"key":"B8-20250823","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/nsmb.3357","article-title":"Molecular insights into lipid-assisted Ca2+ regulation of the TRP channel polycystin-2","volume":"24","author":"Wilkes","year":"2017","journal-title":"Nat Struct Mol Biol"},{"key":"B9-20250823","doi-asserted-by":"crossref","first-page":"e36931","DOI":"10.7554\/eLife.36931","article-title":"Cryo-EM structure of the polycystin 2-l1 ion channel","volume":"7","author":"Hulse","year":"2018","journal-title":"eLife"},{"key":"B10-20250823","doi-asserted-by":"crossref","first-page":"a028209","DOI":"10.1101\/cshperspect.a028209","article-title":"Ciliary mechanisms of cyst formation in polycystic kidney disease","volume":"9","author":"Ma","year":"2017","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"B11-20250823","doi-asserted-by":"crossref","first-page":"e33183","DOI":"10.7554\/eLife.33183","article-title":"Polycystin-2 is an essential ion channel subunit in the primary cilium of the renal collecting duct epithelium","volume":"7","author":"Liu","year":"2018","journal-title":"eLife"},{"key":"B12-20250823","doi-asserted-by":"crossref","first-page":"e49156","DOI":"10.15252\/embr.201949156","article-title":"Holding open the door reveals a new view of polycystin channel function","volume":"20","author":"Caplan","year":"2019","journal-title":"EMBO Rep"},{"key":"B13-20250823","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/ncb754","article-title":"Polycystin-2 is an intracellular calcium release channel","volume":"4","author":"Koulen","year":"2002","journal-title":"Nat Cell Biol"},{"key":"B14-20250823","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/nrneph.2015.39","article-title":"Vasopressin and disruption of calcium signalling in polycystic kidney disease","volume":"11","author":"Chebib","year":"2015","journal-title":"Nat Rev Nephrol"},{"key":"B15-20250823","doi-asserted-by":"crossref","first-page":"40419","DOI":"10.1074\/jbc.M405079200","article-title":"Calcium restriction allows cAMP activation of the B-Raf\/ERK pathway, switching cells to a cAMP-dependent growth-stimulated phenotype","volume":"279","author":"Yamaguchi","year":"2004","journal-title":"J Biol Chem"},{"key":"B16-20250823","doi-asserted-by":"crossref","first-page":"109490","DOI":"10.1016\/j.cellsig.2019.109490","article-title":"Polycystin 2: A calcium channel, channel partner, and regulator of calcium homeostasis in ADPKD","volume":"66","author":"Brill","year":"2020","journal-title":"Cell Signal"},{"key":"B17-20250823","doi-asserted-by":"crossref","first-page":"E2363","DOI":"10.1073\/pnas.1517066113","article-title":"Function and regulation of TRPP2 ion channel revealed by a gain-of-function mutant","volume":"113","author":"Arif Pavel","year":"2016","journal-title":"Proc Natl Acad Sci USA"},{"key":"B18-20250823","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/s00424-012-1197-5","article-title":"TRIC channels supporting efficient Ca(2+) release from intracellular stores","volume":"465","author":"Venturi","year":"2013","journal-title":"Pflugers Arch"},{"key":"B19-20250823","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1161\/CIRCRESAHA.114.301816","article-title":"Trimeric intracellular cation channels and sarcoplasmic\/endoplasmic reticulum calcium homeostasis","volume":"114","author":"Zhou","year":"2014","journal-title":"Circ Res"},{"key":"B20-20250823","doi-asserted-by":"crossref","first-page":"e12821","DOI":"10.1371\/journal.pone.0012821","article-title":"Pkd1 and Pkd2 are required for normal placental development","volume":"5","author":"Garcia-Gonzalez","year":"2010","journal-title":"PLoS One"},{"key":"B21-20250823","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1681\/ASN.2010060681","article-title":"Activation of PI3-kinase stimulates endocytosis of ROMK via Akt1\/SGK1-dependent phosphorylation of WNK1","volume":"22","author":"Cheng","year":"2011","journal-title":"J Am Soc Nephrol"},{"key":"B22-20250823","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1038\/nprot.2013.143","article-title":"Genome engineering using the CRISPR-Cas9 system","volume":"8","author":"Ran","year":"2013","journal-title":"Nat Protoc"},{"key":"B23-20250823","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.ydbio.2017.05.024","article-title":"G\u03b21 is required for neutrophil migration in zebrafish","volume":"428","author":"Ke","year":"2017","journal-title":"Dev Biol"},{"key":"B24-20250823","doi-asserted-by":"crossref","first-page":"2302","DOI":"10.1038\/s41467-018-04586-x","article-title":"Hydrophobic pore gates regulate ion permeation in polycystic kidney disease 2 and 2L1 channels","volume":"9","author":"Zheng","year":"2018","journal-title":"Nat Commun"},{"key":"B25-20250823","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/nprot.2010.165","article-title":"Embedding, serial sectioning and staining of zebrafish embryos using JB-4 resin","volume":"6","author":"Sullivan-Brown","year":"2011","journal-title":"Nat Protoc"},{"key":"B26-20250823","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/71724","article-title":"Cardiac defects and renal failure in mice with targeted mutations in Pkd2","volume":"24","author":"Wu","year":"2000","journal-title":"Nat Genet"},{"key":"B27-20250823","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1016\/j.kint.2020.07.041","article-title":"Mineral bone disease in autosomal dominant polycystic kidney disease","volume":"99","author":"Gitomer","year":"2021","journal-title":"Kidney Int"},{"key":"B28-20250823","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1038\/ng.2715","article-title":"Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease","volume":"45","author":"Ma","year":"2013","journal-title":"Nat Genet"},{"key":"B29-20250823","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1097\/01.ASN.0000016443.50138.CD","article-title":"A minimal Ksp-cadherin promoter linked to a green fluorescent protein reporter gene exhibits tissue-specific expression in the developing kidney and genitourinary tract","volume":"13","author":"Shao","year":"2002","journal-title":"J Am Soc Nephrol"},{"key":"B30-20250823","doi-asserted-by":"crossref","first-page":"4148","DOI":"10.1038\/s41467-019-11918-y","article-title":"Discovery and preclinical evaluation of anti-miR-17 oligonucleotide RGLS4326 for the treatment of polycystic kidney disease","volume":"10","author":"Lee","year":"2019","journal-title":"Nat Commun"},{"key":"B31-20250823","doi-asserted-by":"crossref","first-page":"2355","DOI":"10.1242\/dev.036798","article-title":"Essential role of the TRIC-B channel in Ca2+ handling of alveolar epithelial cells and in perinatal lung maturation","volume":"136","author":"Yamazaki","year":"2009","journal-title":"Development"},{"key":"B32-20250823","doi-asserted-by":"crossref","first-page":"ra49","DOI":"10.1126\/scisignal.aad9055","article-title":"Mice lacking the intracellular cation channel TRIC-B have compromised collagen production and impaired bone mineralization","volume":"9","author":"Zhao","year":"2016","journal-title":"Sci Signal"},{"key":"B33-20250823","doi-asserted-by":"crossref","first-page":"jcs206565","DOI":"10.1242\/jcs.206565","article-title":"Protein localization screening in vivo reveals novel regulators of multiciliated cell development and function","volume":"131","author":"Tu","year":"2018","journal-title":"J Cell Sci"},{"key":"B34-20250823","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1242\/dev.02827","article-title":"Zebrafish curly up encodes a Pkd2 ortholog that restricts left-side-specific expression of southpaw","volume":"134","author":"Schottenfeld","year":"2007","journal-title":"Development"},{"key":"B35-20250823","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1242\/dmm.003194","article-title":"The ADPKD genes pkd1a\/b and pkd2 regulate extracellular matrix formation","volume":"3","author":"Mangos","year":"2010","journal-title":"Dis Model Mech"},{"key":"B36-20250823","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1161\/CIRCRESAHA.119.316241","article-title":"TRIC-A channel maintains store calcium handling by interacting with type 2 ryanodine receptor in cardiac muscle","volume":"126","author":"Zhou","year":"2020","journal-title":"Circ Res"},{"key":"B37-20250823","doi-asserted-by":"crossref","first-page":"4238","DOI":"10.1073\/pnas.1817271116","article-title":"Structural basis for activity of TRIC counter-ion channels in calcium release","volume":"116","author":"Wang","year":"2019","journal-title":"Proc Natl Acad Sci USA"},{"key":"B38-20250823","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1038\/ki.1995.383","article-title":"An ATP-regulated, inwardly rectifying potassium channel from rat kidney (ROMK)","volume":"48","author":"Hebert","year":"1995","journal-title":"Kidney Int"},{"key":"B39-20250823","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1242\/jcs.02818","article-title":"Polycystin-2 traffics to cilia independently of polycystin-1 by using an N-terminal RVxP motif","volume":"119","author":"Geng","year":"2006","journal-title":"J Cell Sci"},{"key":"B40-20250823","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/nature12832","article-title":"Direct recording and molecular identification of the calcium channel of primary cilia","volume":"504","author":"DeCaen","year":"2013","journal-title":"Nature"},{"key":"B41-20250823","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1038\/nm.1865","article-title":"An efficient and versatile system for acute and chronic modulation of renal tubular function in transgenic mice","volume":"14","author":"Traykova-Brauch","year":"2008","journal-title":"Nat Med"},{"key":"B42-20250823","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/j.cub.2019.01.054","article-title":"Tulp3 is a ciliary trafficking gene that regulates polycystic kidney disease","volume":"29","author":"Legu\u00e9","year":"2019","journal-title":"Curr Biol"},{"key":"B43-20250823","doi-asserted-by":"crossref","first-page":"5286","DOI":"10.1073\/pnas.0836980100","article-title":"Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease","volume":"100","author":"Lin","year":"2003","journal-title":"Proc Natl Acad Sci USA"},{"key":"B44-20250823","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.kint.2017.08.005","article-title":"Adenylyl cyclase 5 deficiency reduces renal cyclic AMP and cyst growth in an orthologous mouse model of polycystic kidney disease","volume":"93","author":"Wang","year":"2018","journal-title":"Kidney Int"},{"key":"B45-20250823","doi-asserted-by":"crossref","first-page":"109630","DOI":"10.1016\/j.cellsig.2020.109630","article-title":"Regulation of polycystin expression, maturation and trafficking","volume":"72","author":"Hu","year":"2020","journal-title":"Cell Signal"},{"key":"B46-20250823","doi-asserted-by":"crossref","first-page":"F1165","DOI":"10.1152\/ajprenal.00062.2021","article-title":"Inward Ca2+ current through the polycystin-2-dependent channels of renal primary cilia","volume":"320","author":"Kleene","year":"2021","journal-title":"Am J Physiol Renal Physiol"},{"key":"B47-20250823","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1085\/jgp.201611696","article-title":"Progress in ciliary ion channel physiology","volume":"149","author":"Pablo","year":"2017","journal-title":"J Gen Physiol"},{"key":"B48-20250823","doi-asserted-by":"crossref","first-page":"jcs259013","DOI":"10.1242\/jcs.259013","article-title":"A polycystin-2 protein with modified channel properties leads to an increased diameter of renal tubules and to renal cysts","volume":"134","author":"Grosch","year":"2021","journal-title":"J Cell Sci"},{"key":"B49-20250823","doi-asserted-by":"crossref","first-page":"e1006156","DOI":"10.1371\/journal.pgen.1006156","article-title":"Absence of the ER cation channel TMEM38B\/TRIC-B disrupts intracellular calcium homeostasis and dysregulates collagen synthesis in recessive osteogenesis imperfecta","volume":"12","author":"Cabral","year":"2016","journal-title":"PLoS Genet"},{"key":"B50-20250823","doi-asserted-by":"crossref","first-page":"14283","DOI":"10.1073\/pnas.1412323111","article-title":"Cyst formation following disruption of intracellular calcium signaling","volume":"111","author":"Kuo","year":"2014","journal-title":"Proc Natl Acad Sci USA"},{"key":"B51-20250823","doi-asserted-by":"crossref","first-page":"10329","DOI":"10.1073\/pnas.1920777117","article-title":"Molecular dysregulation of ciliary polycystin-2 channels caused by variants in the TOP domain","volume":"117","author":"Vien","year":"2020","journal-title":"Proc Natl Acad Sci USA"},{"key":"B52-20250823","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/d41573-019-00131-7","article-title":"TRIC-B: An under-explored druggable ion channel","volume":"18","author":"Hu","year":"2019","journal-title":"Nat Rev Drug Discov"}],"container-title":["Journal of the American Society of Nephrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.1681\/ASN.2022010053","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T19:30:23Z","timestamp":1786131023000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.1681\/ASN.2022010053"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8]]},"references-count":52,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2022]]}},"URL":"https:\/\/doi.org\/10.1681\/asn.2022010053","relation":{},"ISSN":["1046-6673","1533-3450"],"issn-type":[{"value":"1046-6673","type":"print"},{"value":"1533-3450","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8]]},"assertion":[{"value":"2022-01-13","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-04-03","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}