{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T02:17:42Z","timestamp":1777688262815,"version":"3.51.4"},"reference-count":63,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T00:00:00Z","timestamp":1679011200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2023,4]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Although hyperpolarization\u2010activated cation (HCN) ion channels are well established to underlie cardiac pacemaker activity, their role in smooth muscle organs remains controversial. HCN\u2010expressing cells are localized to renal pelvic smooth muscle (RPSM) pacemaker tissues of the murine upper urinary tract and HCN channel conductance is required for peristalsis. To date, however, the\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>h<\/jats:sub>\n                      pacemaker current conducted by HCN channels has never been detected in these cells, raising questions on the identity of RPSM pacemakers. Indeed, the RPSM pacemaker mechanisms of the unique multicalyceal upper urinary tract exhibited by humans remains unknown. Here, we developed immunopanning purification protocols and demonstrate that 96% of isolated HCN+ cells exhibit\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>h<\/jats:sub>\n                      . Single\u2010molecule STORM to whole\u2010tissue imaging showed HCN+ cells express single HCN channels on their plasma membrane and integrate into the muscular syncytium. By contrast, PDGFR\u2010\u03b1+ cells exhibiting the morphology of ICC gut pacemakers were shown to be vascular mural cells. Translational studies in the homologous human and porcine multicalyceal upper urinary tracts showed that contractions and pacemaker depolarizations originate in proximal calyceal RPSM. Critically, HCN+ cells were shown to integrate into calyceal RPSM pacemaker tissues, and HCN channel block abolished electrical pacemaker activity and peristalsis of the multicalyceal upper urinary tract. Cumulatively, these studies demonstrate that HCN ion channels play a broad, evolutionarily conserved pacemaker role in both cardiac and smooth muscle organs and have implications for channelopathies as putative aetiologies of smooth muscle disorders.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15467-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Pacemakers trigger contractions of involuntary muscles. Hyperpolarization\u2010activated cation (HCN) ion channels underpin cardiac pacemaker activity, but their role in smooth muscle organs remains controversial.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Renal pelvic smooth muscle (RPSM) pacemakers trigger contractions that propel waste away from the kidney. HCN+ cells localize to murine RPSM pacemaker tissue and HCN channel conductance is required for peristalsis.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            The HCN (\n                            <jats:italic>I<\/jats:italic>\n                            <jats:sub>h<\/jats:sub>\n                            ) current has never been detected in RPSM cells, raising doubt whether HCN+ cells are bona fide pacemakers. Moreover, the pacemaker mechanisms of the unique multicalyceal RPSM of higher order mammals remains unknown.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            In total, 97% of purified HCN+ RPSM cells exhibit\n                            <jats:italic>I<\/jats:italic>\n                            <jats:sub>h<\/jats:sub>\n                            . HCN+ cells integrate into the RPSM musculature, and pacemaker tissue peristalsis is dependent on HCN channels. Translational studies in human and swine demonstrate HCN channels are conserved in the multicalyceal RPSM and that HCN channels underlie pacemaker activity that drives peristalsis.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>These studies provide insight into putative channelopathies that can underlie smooth muscle dysfunction.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp283701","type":"journal-article","created":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T12:55:41Z","timestamp":1679057741000},"page":"1225-1246","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["An evolutionarily conserved pacemaker role for HCN ion channels in smooth muscle"],"prefix":"10.1113","volume":"601","author":[{"given":"Lei","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics Weill Medical College of Cornell University  New York NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodolfo J. Ricart","family":"Arbona","sequence":"additional","affiliation":[{"name":"Center of Comparative Medicine and Pathology Memorial Sloan Kettering Cancer Center  New York NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1581-9855","authenticated-orcid":false,"given":"Carl S.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Urologic Surgery University of Minnesota School of Medicine  Minneapolis MN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly M.","family":"Banks","sequence":"additional","affiliation":[{"name":"Department of Surgery Weill Medical College of Cornell University  New York NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V. Kaye","family":"Thomas","sequence":"additional","affiliation":[{"name":"Bio\u2010Imaging Resource Center The Rockefeller University  New York NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7702-4703","authenticated-orcid":false,"given":"Lawrence","family":"Palmer","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics Weill Medical College of Cornell University  New York NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Todd","family":"Evans","sequence":"additional","affiliation":[{"name":"Department of Surgery Weill Medical College of Cornell University  New York NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0865-3383","authenticated-orcid":false,"given":"Romulo","family":"Hurtado","sequence":"additional","affiliation":[{"name":"Department of Surgery Weill Medical College of Cornell University  New York NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,3,17]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13052-016-0316-x"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1101\/pdb.ip073999"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/prca.201300099"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbiomolbio.2021.08.007"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00029.2008"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1993.tb13815.x"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI45523"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-014-1549-4"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-013-2862-2"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.434803"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000265845.04439.78"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1999.515ae.x"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1986.sp016177"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-013-2631-4"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00074.2009"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01937802"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP278888"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(86)83467-1"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP270818"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2015.00293"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.00947"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1999.459ae.x"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-016-1930-6"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11255-018-1816-y"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2018060644"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2001.014803"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2003.043299"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2009.483"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.13-237289"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/joa.12444"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2009.176198"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2011.01730.x"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.18.12835"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2017090951"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.116.018011"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2000.279.3.H1421"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-018-5259-1"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.091844"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8167.2010.01844.x"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-213X-11-43"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1114\/B:ABME.0000039354.41647.1b"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(75)91145-9"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg032"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/18.9.2323"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-199306000-00008"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M502696200"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5347(17)45551-0"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.2003.02634.x"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10840-016-0137-2"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1111\/1440-1681.12288"},{"key":"e_1_2_5_52_1","volume-title":"Nephrons and kidneys; a quantitative study of developmental and evolutionary mammalian renal architectonics","author":"Oliver J.","year":"1968"},{"key":"e_1_2_5_53_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000114527.10764.CC"},{"key":"e_1_2_5_54_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000059939.97249.2C"},{"key":"e_1_2_5_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-82775-3"},{"key":"e_1_2_5_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth929"},{"key":"e_1_2_5_57_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.117.014035"},{"key":"e_1_2_5_58_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.117.2.91"},{"key":"e_1_2_5_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2015.10.004"},{"key":"e_1_2_5_60_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00410188"},{"key":"e_1_2_5_61_1","doi-asserted-by":"publisher","DOI":"10.1159\/000280775"},{"key":"e_1_2_5_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-018-0031-y"},{"key":"e_1_2_5_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(03)75081-4"},{"key":"e_1_2_5_64_1","first-page":"R788","article-title":"Renal calyceal and pelvic contraction rhythms","volume":"257","author":"Yamaguchi O. A.","year":"1989","journal-title":"The American Journal of Physiology"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP283701","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/JP283701","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP283701","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T23:26:27Z","timestamp":1692487587000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP283701"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,17]]},"references-count":63,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2023,4]]}},"alternative-id":["10.1113\/JP283701"],"URL":"https:\/\/doi.org\/10.1113\/jp283701","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.08.14.503722","asserted-by":"object"}]},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,17]]},"assertion":[{"value":"2022-08-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-02-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-03-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}