{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T12:16:56Z","timestamp":1762604216060,"version":"3.41.2"},"reference-count":73,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,6,11]],"date-time":"2020-06-11T00:00:00Z","timestamp":1591833600000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001543","name":"Neurological Foundation of New Zealand","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001543","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001505","name":"Health Research Council of New Zealand","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001505","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001511","name":"Auckland Medical Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001511","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001509","name":"Royal Society of New Zealand","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001509","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2020,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The corticotropin\u2010releasing factor (CRF) receptors represent potential drug targets for the treatment of anxiety, stress, and other disorders. However, it is not known if endogenous CRF receptor agonists display biased signaling, how effective CRF receptor antagonists are at blocking different agonists and signaling pathways or how receptor activity\u2010modifying proteins (RAMPs) effect these processes. This study aimed to address this by investigating agonist and antagonist action at CRF<jats:sub>1<\/jats:sub> and CRF<jats:sub>2<\/jats:sub> receptors. We used CRF<jats:sub>1<\/jats:sub> and CRF<jats:sub>2<\/jats:sub> receptor transfected Cos7 cells to assess the ability of CRF and urocortin (UCN) peptides to activate cAMP, inositol monophosphate (IP<jats:sub>1<\/jats:sub>), and extracellular signal\u2010regulated kinase 1\/2 signaling and determined the ability of antagonists to block agonist\u2010stimulated cAMP and IP<jats:sub>1<\/jats:sub> accumulation. The ability of RAMPs to interact with CRF receptors was also examined. At the CRF<jats:sub>1<\/jats:sub> receptor, CRF and UCN1 activated signaling in the same manner. However, at the CRF<jats:sub>2<\/jats:sub> receptor, UCN1 and UCN2 displayed similar signaling profiles, whereas CRF and UCN3 displayed bias away from IP<jats:sub>1<\/jats:sub> accumulation over cAMP. The antagonist potency was dependent on the receptor, agonist, and signaling pathway. CRF<jats:sub>1<\/jats:sub> and CRF<jats:sub>2<\/jats:sub> receptors had no effect on RAMP1 or RAMP2 surface expression. The presence of biased agonism and agonist\u2010dependent antagonism at the CRF receptors offers new avenues for developing drugs tailored to activate a specific signaling pathway or block a specific agonist. Our findings suggest that the already complex CRF receptor pharmacology may be underappreciated and requires further investigation.<\/jats:p>","DOI":"10.1002\/prp2.595","type":"journal-article","created":{"date-parts":[[2020,6,12]],"date-time":"2020-06-12T05:20:36Z","timestamp":1591939236000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Agonist bias and agonist\u2010dependent antagonism at corticotrophin releasing factor receptors"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7652-6004","authenticated-orcid":false,"given":"Zoe","family":"Tasma","sequence":"first","affiliation":[{"name":"School of Biological Sciences University of Auckland Auckland New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Wills","sequence":"additional","affiliation":[{"name":"School of Biological Sciences University of Auckland Auckland New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9558-5122","authenticated-orcid":false,"given":"Debbie L.","family":"Hay","sequence":"additional","affiliation":[{"name":"School of Biological Sciences University of Auckland Auckland New Zealand"},{"name":"Maurice Wilkins Centre and Centre for Brain Research University of Auckland Auckland New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8151-4123","authenticated-orcid":false,"given":"Christopher S.","family":"Walker","sequence":"additional","affiliation":[{"name":"School of Biological Sciences University of Auckland Auckland New Zealand"},{"name":"Maurice Wilkins Centre and Centre for Brain Research University of Auckland Auckland New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,6,11]]},"reference":[{"doi-asserted-by":"publisher","key":"e_1_2_9_2_1","DOI":"10.2174\/138945012798868434"},{"doi-asserted-by":"publisher","key":"e_1_2_9_3_1","DOI":"10.1073\/pnas.78.10.6517"},{"doi-asserted-by":"publisher","key":"e_1_2_9_4_1","DOI":"10.1210\/endo.135.5.7956950"},{"doi-asserted-by":"publisher","key":"e_1_2_9_5_1","DOI":"10.1111\/bph.14748"},{"doi-asserted-by":"publisher","key":"e_1_2_9_6_1","DOI":"10.3389\/fnins.2013.00169"},{"doi-asserted-by":"publisher","key":"e_1_2_9_7_1","DOI":"10.1038\/nrn.2016.94"},{"doi-asserted-by":"publisher","key":"e_1_2_9_8_1","DOI":"10.1002\/ardp.200600021"},{"doi-asserted-by":"publisher","key":"e_1_2_9_9_1","DOI":"10.1073\/pnas.1013761107"},{"doi-asserted-by":"publisher","key":"e_1_2_9_10_1","DOI":"10.1038\/378287a0"},{"doi-asserted-by":"publisher","key":"e_1_2_9_11_1","DOI":"10.1152\/physrev.00042.2017"},{"doi-asserted-by":"publisher","key":"e_1_2_9_12_1","DOI":"10.1111\/j.1476-5381.2012.01904.x"},{"doi-asserted-by":"publisher","key":"e_1_2_9_13_1","DOI":"10.1093\/eurheartj\/ehi227"},{"doi-asserted-by":"publisher","key":"e_1_2_9_14_1","DOI":"10.1073\/pnas.0611641104"},{"doi-asserted-by":"publisher","key":"e_1_2_9_15_1","DOI":"10.1016\/j.tem.2007.12.002"},{"doi-asserted-by":"publisher","key":"e_1_2_9_16_1","DOI":"10.1007\/s00441-018-2962-3"},{"key":"e_1_2_9_17_1","first-page":"113","article-title":"Different binding modes of amphibian and human corticotropin\u2010releasing factor type 1 and type 2 receptors: evidence for evolutionary differences","volume":"296","author":"Dautzenberg FM","year":"2001","journal-title":"J Pharmacol Exp Ther"},{"doi-asserted-by":"publisher","key":"e_1_2_9_18_1","DOI":"10.1124\/pr.55.1.3"},{"doi-asserted-by":"publisher","key":"e_1_2_9_19_1","DOI":"10.1016\/j.drudis.2010.02.011"},{"doi-asserted-by":"publisher","key":"e_1_2_9_20_1","DOI":"10.1111\/j.1476-5381.2012.02202.x"},{"doi-asserted-by":"publisher","key":"e_1_2_9_21_1","DOI":"10.1111\/j.1476-5381.2011.01571.x"},{"doi-asserted-by":"publisher","key":"e_1_2_9_22_1","DOI":"10.1016\/j.bbamem.2019.02.008"},{"doi-asserted-by":"publisher","key":"e_1_2_9_23_1","DOI":"10.1126\/sciadv.aaw2778"},{"doi-asserted-by":"publisher","key":"e_1_2_9_24_1","DOI":"10.1042\/BST20150237"},{"doi-asserted-by":"publisher","key":"e_1_2_9_25_1","DOI":"10.1038\/nrm2803"},{"doi-asserted-by":"publisher","key":"e_1_2_9_26_1","DOI":"10.2174\/138955712800959071"},{"doi-asserted-by":"publisher","key":"e_1_2_9_27_1","DOI":"10.1038\/nrd3954"},{"doi-asserted-by":"publisher","key":"e_1_2_9_28_1","DOI":"10.1124\/mol.104.008615"},{"doi-asserted-by":"publisher","key":"e_1_2_9_29_1","DOI":"10.1111\/j.1476-5381.2012.02197.x"},{"doi-asserted-by":"publisher","key":"e_1_2_9_30_1","DOI":"10.1111\/bph.12541"},{"doi-asserted-by":"publisher","key":"e_1_2_9_31_1","DOI":"10.1016\/j.bcp.2017.07.005"},{"doi-asserted-by":"publisher","key":"e_1_2_9_32_1","DOI":"10.1177\/0333102417691762"},{"doi-asserted-by":"publisher","key":"e_1_2_9_33_1","DOI":"10.1111\/bph.12508"},{"doi-asserted-by":"publisher","key":"e_1_2_9_34_1","DOI":"10.1124\/mol.113.088880"},{"volume-title":"A Pharmacology Primer: Techniques for More Effective and Strategic Drug Discovery","year":"2014","author":"Kenakin TP","key":"e_1_2_9_35_1"},{"doi-asserted-by":"publisher","key":"e_1_2_9_36_1","DOI":"10.1016\/j.tips.2007.06.004"},{"doi-asserted-by":"publisher","key":"e_1_2_9_37_1","DOI":"10.1016\/j.molcel.2015.04.018"},{"doi-asserted-by":"publisher","key":"e_1_2_9_38_1","DOI":"10.1111\/bph.14153"},{"doi-asserted-by":"publisher","key":"e_1_2_9_39_1","DOI":"10.1016\/j.neuropharm.2009.06.022"},{"doi-asserted-by":"publisher","key":"e_1_2_9_40_1","DOI":"10.1111\/j.1749-6632.2009.05011.x"},{"doi-asserted-by":"publisher","key":"e_1_2_9_41_1","DOI":"10.1111\/bph.13878"},{"doi-asserted-by":"publisher","key":"e_1_2_9_42_1","DOI":"10.1021\/jm0202122"},{"doi-asserted-by":"publisher","key":"e_1_2_9_43_1","DOI":"10.1021\/jm070579c"},{"key":"e_1_2_9_44_1","first-page":"729","article-title":"Comparison of an agonist, urocortin, and an antagonist, astressin, as radioligands for characterization of corticotropin\u2010releasing factor receptors","volume":"288","author":"Perrin MH","year":"1999","journal-title":"J Pharmacol Exp Ther"},{"doi-asserted-by":"publisher","key":"e_1_2_9_45_1","DOI":"10.1016\/S0014-2999(99)00506-3"},{"doi-asserted-by":"publisher","key":"e_1_2_9_46_1","DOI":"10.1038\/nature12357"},{"doi-asserted-by":"publisher","key":"e_1_2_9_47_1","DOI":"10.1038\/365170a0"},{"doi-asserted-by":"publisher","key":"e_1_2_9_48_1","DOI":"10.1016\/j.bcp.2018.09.003"},{"doi-asserted-by":"publisher","key":"e_1_2_9_49_1","DOI":"10.1016\/j.cell.2016.05.023"},{"doi-asserted-by":"publisher","key":"e_1_2_9_50_1","DOI":"10.1111\/bph.12445"},{"doi-asserted-by":"publisher","key":"e_1_2_9_51_1","DOI":"10.1016\/j.bcp.2004.07.013"},{"doi-asserted-by":"publisher","key":"e_1_2_9_52_1","DOI":"10.1016\/j.brainres.2015.11.021"},{"doi-asserted-by":"publisher","key":"e_1_2_9_53_1","DOI":"10.1046\/j.0022-3042.2001.00712.x"},{"doi-asserted-by":"publisher","key":"e_1_2_9_54_1","DOI":"10.1210\/en.2003-1023"},{"doi-asserted-by":"publisher","key":"e_1_2_9_55_1","DOI":"10.1210\/me.14.12.2076"},{"doi-asserted-by":"publisher","key":"e_1_2_9_56_1","DOI":"10.1210\/me.2006-0255"},{"doi-asserted-by":"publisher","key":"e_1_2_9_57_1","DOI":"10.1016\/j.bbamcr.2011.02.005"},{"doi-asserted-by":"publisher","key":"e_1_2_9_58_1","DOI":"10.1016\/j.peptides.2006.03.022"},{"doi-asserted-by":"publisher","key":"e_1_2_9_59_1","DOI":"10.1038\/sj.bjp.0706926"},{"doi-asserted-by":"publisher","key":"e_1_2_9_60_1","DOI":"10.1016\/j.peptides.2004.10.019"},{"key":"e_1_2_9_61_1","first-page":"846","article-title":"Differential actions of corticotropin releasing factor on basolateral and central amygdaloid neurones, in vitro","volume":"263","author":"Rainnie DG","year":"1992","journal-title":"J Pharmacol Exp Ther"},{"doi-asserted-by":"publisher","key":"e_1_2_9_62_1","DOI":"10.1002\/syn.890010610"},{"doi-asserted-by":"publisher","key":"e_1_2_9_63_1","DOI":"10.1111\/j.1527-3458.2005.tb00034.x"},{"doi-asserted-by":"publisher","key":"e_1_2_9_64_1","DOI":"10.1111\/j.1476-5381.2011.01390.x"},{"doi-asserted-by":"publisher","key":"e_1_2_9_65_1","DOI":"10.1016\/j.tips.2013.11.001"},{"doi-asserted-by":"publisher","key":"e_1_2_9_66_1","DOI":"10.1002\/acn3.197"},{"doi-asserted-by":"publisher","key":"e_1_2_9_67_1","DOI":"10.1016\/j.neuroscience.2010.05.016"},{"doi-asserted-by":"publisher","key":"e_1_2_9_68_1","DOI":"10.1074\/jbc.M114.624601"},{"doi-asserted-by":"publisher","key":"e_1_2_9_69_1","DOI":"10.1210\/en.2016-1755"},{"doi-asserted-by":"publisher","key":"e_1_2_9_70_1","DOI":"10.1074\/jbc.C200629200"},{"doi-asserted-by":"publisher","key":"e_1_2_9_71_1","DOI":"10.1074\/jbc.M302571200"},{"doi-asserted-by":"publisher","key":"e_1_2_9_72_1","DOI":"10.1016\/j.peptides.2005.11.014"},{"doi-asserted-by":"publisher","key":"e_1_2_9_73_1","DOI":"10.1371\/journal.pone.0109503"},{"doi-asserted-by":"publisher","key":"e_1_2_9_74_1","DOI":"10.1093\/nar\/gkv1037"}],"container-title":["Pharmacology Research &amp; Perspectives"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fprp2.595","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prp2.595","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/prp2.595","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prp2.595","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T03:19:21Z","timestamp":1693970361000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1002\/prp2.595"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6]]},"references-count":73,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2020,6]]}},"alternative-id":["10.1002\/prp2.595"],"URL":"https:\/\/doi.org\/10.1002\/prp2.595","archive":["Portico"],"relation":{},"ISSN":["2052-1707","2052-1707"],"issn-type":[{"type":"print","value":"2052-1707"},{"type":"electronic","value":"2052-1707"}],"subject":[],"published":{"date-parts":[[2020,6]]},"assertion":[{"value":"2020-03-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-03-26","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-06-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00595"}}