{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T18:17:08Z","timestamp":1783448228185,"version":"3.55.0"},"reference-count":35,"publisher":"Bioscientifica","issue":"1_Suppl","license":[{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"vor","delay-in-days":3917,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"}],"content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2015,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Background: 3-Iodothyronamine (3-T&amp;lt;sub&amp;gt;1&amp;lt;\/sub&amp;gt;AM), a signaling molecule with structural similarities to thyroid hormones, induces numerous physiological responses including reversible body temperature decline. One target of 3-T&amp;lt;sub&amp;gt;1&amp;lt;\/sub&amp;gt;AM is the trace amine-associated receptor 1 (TAAR1), which is a member of the rhodopsin-like family of G protein-coupled receptors (GPCRs). Interestingly, the effects of 3-T&amp;lt;sub&amp;gt;1&amp;lt;\/sub&amp;gt;AM remain detectable in TAAR1 knockout mice, suggesting further targets for 3-T&amp;lt;sub&amp;gt;1&amp;lt;\/sub&amp;gt;AM such as adrenergic receptors. Therefore, we evaluated whether \u03b2-adrenergic receptor 1 (ADRB1) and 2 (ADRB2) signaling is affected by 3-T&amp;lt;sub&amp;gt;1&amp;lt;\/sub&amp;gt;AM in HEK293 cells and in human conjunctival epithelial cells (IOBA-NHC), where these receptors are highly expressed endogenously. Methods: A label-free EPIC system for prescreening the 3-T&amp;lt;sub&amp;gt;1&amp;lt;\/sub&amp;gt;AM-induced effects on ADRB1 and ADRB2 in transfected HEK293 cells was used. In addition, ADRB1 and ADRB2 activation was analyzed using a cyclic AMP assay and a MAPK reporter gene assay. Finally, fluorescence Ca&amp;lt;sup&amp;gt;2+&amp;lt;\/sup&amp;gt; imaging was utilized to delineate 3-T&amp;lt;sub&amp;gt;1&amp;lt;\/sub&amp;gt;AM-induced Ca&amp;lt;sup&amp;gt;2+&amp;lt;\/sup&amp;gt; signaling. Results: 3-T&amp;lt;sub&amp;gt;1&amp;lt;\/sub&amp;gt;AM (10&amp;lt;sup&amp;gt;-5&amp;lt;\/sup&amp;gt;- 10&amp;lt;sup&amp;gt;-10&amp;lt;\/sup&amp;gt;&amp;lt;smlcap&amp;gt;M&amp;lt;\/smlcap&amp;gt;) enhanced isoprenaline-induced ADRB2-mediated G&amp;lt;sub&amp;gt;s&amp;lt;\/sub&amp;gt; signaling but not that of ADRB1-mediated signaling. MAPK signaling remained unaffected for both receptors. In IOBA-NHC cells, norepinephrine-induced Ca&amp;lt;sup&amp;gt;2+&amp;lt;\/sup&amp;gt; influxes were blocked by the nonselective ADRB blocker timolol (10 \u00b5&amp;lt;smlcap&amp;gt;M&amp;lt;\/smlcap&amp;gt;), indicating that ADRBs are most likely linked with Ca&amp;lt;sup&amp;gt;2+&amp;lt;\/sup&amp;gt; channels. Notably, timolol was also found to block 3-T&amp;lt;sub&amp;gt;1&amp;lt;\/sub&amp;gt;AM (10&amp;lt;sup&amp;gt;-5&amp;lt;\/sup&amp;gt;&amp;lt;smlcap&amp;gt;M&amp;lt;\/smlcap&amp;gt;)-induced Ca&amp;lt;sup&amp;gt;2+&amp;lt;\/sup&amp;gt; influx. Conclusions: The presented data support that 3-T&amp;lt;sub&amp;gt;1&amp;lt;\/sub&amp;gt;AM directly modulates \u03b2-adrenergic receptor signaling. The relationship between 3-T&amp;lt;sub&amp;gt;1&amp;lt;\/sub&amp;gt;AM and \u03b2-adrenergic signaling also reveals a potential therapeutic value for suppressing Ca&amp;lt;sup&amp;gt;2+&amp;lt;\/sup&amp;gt; channel-mediated inflammation processes, occurring in eye diseases such as conjunctivitis.<\/jats:p>","DOI":"10.1159\/000381801","type":"journal-article","created":{"date-parts":[[2015,5,28]],"date-time":"2015-05-28T17:20:21Z","timestamp":1432833621000},"page":"21-29","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-17","source":"Crossref","is-referenced-by-count":24,"title":["The Multitarget Ligand 3-Iodothyronamine Modulates \u03b2-Adrenergic Receptor 2 Signaling"],"prefix":"10.1530","volume":"4","author":[{"given":"Juliane","family":"Dinter","sequence":"first","affiliation":[{"name":"1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noushafarin","family":"Khajavi","sequence":"additional","affiliation":[{"name":"2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"M\u00fchlhaus","sequence":"additional","affiliation":[{"name":"1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolin Leonie","family":"Wienchol","sequence":"additional","affiliation":[{"name":"1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxi","family":"C\u00f6ster","sequence":"additional","affiliation":[{"name":"4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Hermsdorf","sequence":"additional","affiliation":[{"name":"4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"St\u00e4ubert","sequence":"additional","affiliation":[{"name":"4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9187-9078","authenticated-orcid":false,"given":"Josef","family":"K\u00f6hrle","sequence":"additional","affiliation":[{"name":"3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torsten","family":"Sch\u00f6neberg","sequence":"additional","affiliation":[{"name":"4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunnar","family":"Kleinau","sequence":"additional","affiliation":[{"name":"1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Mergler","sequence":"additional","affiliation":[{"name":"2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"Biebermann","sequence":"additional","affiliation":[{"name":"1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2015,5,29]]},"reference":[{"key":"2026070713070507400_ref1","doi-asserted-by":"crossref","unstructured":"Scanlan TS: Minireview: 3-iodothyronamine (T1AM): a new player on the thyroid endocrine team? Endocrinology 2009;150:1108-1111.10.1210\/en.2008-159619116337","DOI":"10.1210\/en.2008-1596"},{"key":"2026070713070507400_ref2","doi-asserted-by":"crossref","unstructured":"Zucchi R, Accorroni A, Chiellini G: Update on 3-iodothyronamine and its neurological and metabolic actions. Front Physiol 2014;5:402.10.3389\/fphys.2014.0040225360120","DOI":"10.3389\/fphys.2014.00402"},{"key":"2026070713070507400_ref3","doi-asserted-by":"crossref","unstructured":"Piehl S, Hoefig CS, Scanlan TS, Kohrle J: Thyronamines - past, present, and future. Endocr Rev 2011;32:64-80.10.1210\/er.2009-004020880963","DOI":"10.1210\/er.2009-0040"},{"key":"2026070713070507400_ref4","doi-asserted-by":"crossref","unstructured":"Scanlan TS, Suchland KL, Hart ME, Chiellini G, Huang Y, Kruzich PJ, Frascarelli S, Crossley DA, Bunzow JR, Ronca-Testoni S, Lin ET, Hatton D, Zucchi R, Grandy DK: 3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone. Nat Med 2004;10:638-642.10.1038\/nm105115146179","DOI":"10.1038\/nm1051"},{"key":"2026070713070507400_ref5","doi-asserted-by":"crossref","unstructured":"Cody V, Meyer T, Dohler KD, Hesch RD, Rokos H, Marko M: Molecular structure and biochemical activity of 3,5,3\u2032-triiodothyronamine. Endocr Res 1984;10:91-99.10.3109\/074358084090354106094171","DOI":"10.3109\/07435808409035410"},{"key":"2026070713070507400_ref6","doi-asserted-by":"crossref","unstructured":"Gompf HS, Mathai C, Fuller PM, Wood DA, Pedersen NP, Saper CB, Lu J: Locus ceruleus and anterior cingulate cortex sustain wakefulness in a novel environment. J Neurosci 2010;30:14543-14551.10.1523\/JNEUROSCI.3037-10.201020980612","DOI":"10.1523\/JNEUROSCI.3037-10.2010"},{"key":"2026070713070507400_ref7","doi-asserted-by":"crossref","unstructured":"Khajavi N, Reinach PS, Slavi N, Skrzypski M, Lucius A, Strauss O, Kohrle J, Mergler S: Thyronamine induces TRPM8 channel activation in human conjunctival epithelial cells. Cell Signal 2015;27:315-325.10.1016\/j.cellsig.2014.11.01525460045","DOI":"10.1016\/j.cellsig.2014.11.015"},{"key":"2026070713070507400_ref8","doi-asserted-by":"crossref","unstructured":"Mergler S, Mertens C, Valtink M, Reinach PS, Szekely VC, Slavi N, Garreis F, Abdelmessih S, Turker E, Fels G, Pleyer U: Functional significance of thermosensitive transient receptor potential melastatin channel 8 (TRPM8) expression in immortalized human corneal endothelial cells. Exp Eye Res 2013;116:337-349.10.1016\/j.exer.2013.10.00324135298","DOI":"10.1016\/j.exer.2013.10.003"},{"key":"2026070713070507400_ref9","doi-asserted-by":"crossref","unstructured":"Parra A, Madrid R, Echevarria D, del Olmo S, Morenilla-Palao C, Acosta MC, Gallar J, Dhaka A, Viana F, Belmonte C: Ocular surface wetness is regulated by TRPM8-dependent cold thermoreceptors of the cornea. Nat Med 2010;16:1396-1399.10.1038\/nm.226421076394","DOI":"10.1038\/nm.2264"},{"key":"2026070713070507400_ref10","doi-asserted-by":"crossref","unstructured":"Mergler S, Valtink M, Takayoshi S, Okada Y, Miyajima M, Saika S, Reinach PS: Temperature-sensitive transient receptor potential channels in corneal tissue layers and cells. Ophthalmic Res 2014;52:151-159.10.1159\/00036533425301091","DOI":"10.1159\/000365334"},{"key":"2026070713070507400_ref11","doi-asserted-by":"crossref","unstructured":"Pan Z, Wang Z, Yang H, Zhang F, Reinach PS: TRPV1 activation is required for hypertonicity-stimulated inflammatory cytokine release in human corneal epithelial cells. Invest Ophthalmol Vis Sci 2011;52:485-493.10.1167\/iovs.10-580120739465","DOI":"10.1167\/iovs.10-5801"},{"key":"2026070713070507400_ref12","doi-asserted-by":"crossref","unstructured":"Khajavi N, Reinach PS, Skrzypski M, Lude A, Mergler S: &lt;span style=\"font-variant:small-caps; text-transform:lowercase\"&gt;L&lt;\/span&gt;-Carnitine reduces in human conjunctival epithelial cells hypertonic-induced shrinkage through interacting with TRPV1 channels. Cell Physiol Biochem 2014;34:790-803.25170901","DOI":"10.1159\/000363043"},{"key":"2026070713070507400_ref13","doi-asserted-by":"crossref","unstructured":"Matsuo T, Cynader MS: Localization of \u03b12- adrenergic receptors in the human eye. Ophthalmic Res 1992;24:213-219.10.1159\/0002671701359487","DOI":"10.1159\/000267170"},{"key":"2026070713070507400_ref14","doi-asserted-by":"crossref","unstructured":"Messina Baas O, Pacheco Cuellar G, Toral-Lopez J, Lara Huerta SF, Gonzalez-Huerta LM, Urueta-Cuellar H, Rivera-Vega MR, Babayan-Mena I, Cuevas-Covarrubias SA: ADRB1 and ADBR2 gene polymorphisms and the ocular hypotensive response to topical betaxolol in healthy Mexican subjects. Curr Eye Res 2014;39:1076-1080.10.3109\/02713683.2014.90080724749907","DOI":"10.3109\/02713683.2014.900807"},{"key":"2026070713070507400_ref15","unstructured":"Neufeld AH, Zawistowski KA, Page ED, Bromberg BB: Influences on the density of \u03b2-adrenergic receptors in the cornea and iris - ciliary body of the rabbit. Invest Ophthalmol Vis Sci 1978;17:1069-1075.212382"},{"key":"2026070713070507400_ref16","doi-asserted-by":"crossref","unstructured":"M\u00fchlhaus J, Dinter J, N\u00fcrnberg D, Rehders M, Depke M, Golchert J, Homuth G, Yi CX, Morin S, K\u00f6hrle J, Brix K, Tschop M, Kleinau G, Biebermann H: Analysis of human TAAR8 and murine Taar8b mediated signaling pathways and expression profile. Int J Mol Sci 2014;15:20638-20655.10.3390\/ijms15112063825391046","DOI":"10.3390\/ijms151120638"},{"key":"2026070713070507400_ref17","doi-asserted-by":"crossref","unstructured":"Mergler S, Garreis F, Sahlmuller M, Lyras EM, Reinach PS, Dwarakanath A, Paulsen F, Pleyer U: Calcium regulation by thermo- and osmosensing transient receptor potential vanilloid channels (TRPVs) in human conjunctival epithelial cells. Histochem Cell Biol 2012;137:743-761.10.1007\/s00418-012-0924-522327830","DOI":"10.1007\/s00418-012-0924-5"},{"key":"2026070713070507400_ref18","doi-asserted-by":"crossref","unstructured":"Schr\u00f6der R, Janssen N, Schmidt J, Kebig A, Merten N, Hennen S, M\u00fcller A, Bl\u00e4ttermann S, Mohr-Andr\u00e4 M, Zahn S, Wenzel J, Smith NJ, Gomeza J, Drewke C, Milligan G, Mohr K, Kostenis E: Deconvolution of complex G protein-coupled receptor signaling in live cells using dynamic mass redistribution measurements. Nat Biotechnol 2010;28:943-949.10.1038\/nbt.167120711173","DOI":"10.1038\/nbt.1671"},{"key":"2026070713070507400_ref19","doi-asserted-by":"crossref","unstructured":"Piechowski CL, Rediger A, Lagemann C, M\u00fchlhaus J, Muller A, Pratzka J, Tarnow P, Gr\u00fcters A, Krude H, Kleinau G, Biebermann H: Inhibition of melanocortin-4 receptor dimerization by substitutions in intracellular loop 2. J Mol Endocrinol 2013;51:109-118.10.1530\/JME-13-006123674133","DOI":"10.1530\/JME-13-0061"},{"key":"2026070713070507400_ref20","doi-asserted-by":"crossref","unstructured":"Grynkiewicz G, Poenie M, Tsien RY: A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 1985;260:3440-3450.3838314","DOI":"10.1016\/S0021-9258(19)83641-4"},{"key":"2026070713070507400_ref21","doi-asserted-by":"crossref","unstructured":"Frielle T, Daniel KW, Caron MG, Lefkowitz RJ: Structural basis of \u03b2-adrenergic receptor subtype specificity studied with chimeric \u03b21\/\u03b22-adrenergic receptors. Proc Natl Acad Sci USA 1988;85:9494-9498.10.1073\/pnas.85.24.94942849109","DOI":"10.1073\/pnas.85.24.9494"},{"key":"2026070713070507400_ref22","doi-asserted-by":"crossref","unstructured":"Diebold Y, Calonge M, Enriquez de Salamanca A, Callejo S, Corrales RM, Saez V, Siemasko KF, Stern ME: Characterization of a spontaneously immortalized cell line (IOBA-NHC) from normal human conjunctiva. Invest Ophthalmol Vis Sci 2003;44:4263-4274.10.1167\/iovs.03-056014507870","DOI":"10.1167\/iovs.03-0560"},{"key":"2026070713070507400_ref23","doi-asserted-by":"crossref","unstructured":"Enriquez de Salamanca A, Siemasko KF, Diebold Y, Calonge M, Gao J, Juarez-Campo M, Stern ME: Expression of muscarinic and adrenergic receptors in normal human conjunctival epithelium. Invest Ophthalmol Vis Sci 2005;46:504-513.10.1167\/iovs.04-066515671275","DOI":"10.1167\/iovs.04-0665"},{"key":"2026070713070507400_ref24","doi-asserted-by":"crossref","unstructured":"Regard JB, Sato IT, Coughlin SR: Anatomical profiling of G protein-coupled receptor expression. Cell 2008;135:561-571.10.1016\/j.cell.2008.08.04018984166","DOI":"10.1016\/j.cell.2008.08.040"},{"key":"2026070713070507400_ref25","doi-asserted-by":"crossref","unstructured":"Bavencoffe A, Gkika D, Kondratskyi A, Beck B, Borowiec AS, Bidaux G, Busserolles J, Eschalier A, Shuba Y, Skryma R, Prevarskaya N: The transient receptor potential channel TRPM8 is inhibited via the alpha 2a adrenoreceptor signaling pathway. J Biol Chem 2010;285:9410-9419.10.1074\/jbc.M109.06937720110357","DOI":"10.1074\/jbc.M109.069377"},{"key":"2026070713070507400_ref26","doi-asserted-by":"crossref","unstructured":"Smith NJ, Milligan G: Allostery at G protein-coupled receptor homo- and heteromers: uncharted pharmacological landscapes. Pharmacol Rev 2010;62:701-725.10.1124\/pr.110.00266721079041","DOI":"10.1124\/pr.110.002667"},{"key":"2026070713070507400_ref27","doi-asserted-by":"crossref","unstructured":"Sartania N, Appelbe S, Pediani JD, Milligan G: Agonist occupancy of a single monomeric element is sufficient to cause internalization of the dimeric \u03b22-adrenoceptor. Cell Signal 2007;19:1928-1938.10.1016\/j.cellsig.2007.05.00217561373","DOI":"10.1016\/j.cellsig.2007.05.002"},{"key":"2026070713070507400_ref28","doi-asserted-by":"crossref","unstructured":"Heitman LH, Kleinau G, Brussee J, Krause G, Ijzerman AP: Determination of different putative allosteric binding pockets at the lutropin receptor by using diverse drug-like low molecular weight ligands. Mol Cell Endocrinol 2012;351:326-336.10.1016\/j.mce.2012.01.01022269095","DOI":"10.1016\/j.mce.2012.01.010"},{"key":"2026070713070507400_ref29","doi-asserted-by":"crossref","unstructured":"Thor D, Schulz A, Hermsdorf T, Sch\u00f6neberg T: Generation of an agonistic binding site for blockers of the M3 muscarinic acetylcholine receptor. Biochem J 2008;412:103-112.10.1042\/bj2007136618237275","DOI":"10.1042\/BJ20071366"},{"key":"2026070713070507400_ref30","doi-asserted-by":"crossref","unstructured":"Baker JG, Hill SJ: Multiple GPCR conformations and signalling pathways: implications for antagonist affinity estimates. Trends Pharmacol Sci 2007;28:374-381.10.1016\/j.tips.2007.06.01117629959","DOI":"10.1016\/j.tips.2007.06.011"},{"key":"2026070713070507400_ref31","doi-asserted-by":"crossref","unstructured":"Wenzel-Seifert K, Seifert R: Molecular analysis of \u03b22-adrenoceptor coupling to Gs-, Gi-, and Gq-proteins. Mol Pharmacol 2000;58:954-966.11040042","DOI":"10.1016\/S0026-895X(24)12467-4"},{"key":"2026070713070507400_ref32","doi-asserted-by":"crossref","unstructured":"Ghelardoni S, Suffredini S, Frascarelli S, Brogioni S, Chiellini G, Ronca-Testoni S, Grandy DK, Scanlan TS, Cerbai E, Zucchi R: Modulation of cardiac ionic homeostasis by 3-iodothyronamine. J Cell Mol Med 2009;13:3082-3090.10.1111\/j.1582-4934.2009.00728.x19298522","DOI":"10.1111\/j.1582-4934.2009.00728.x"},{"key":"2026070713070507400_ref33","doi-asserted-by":"crossref","unstructured":"Veldhuis NA, Poole DP, Grace M, McIntyre P, Bunnett NW: The G protein-coupled receptor-transient receptor potential channel axis: molecular insights for targeting disorders of sensation and inflammation. Pharmacol Rev 2015;67:36-73.10.1124\/pr.114.00955525361914","DOI":"10.1124\/pr.114.009555"},{"key":"2026070713070507400_ref34","doi-asserted-by":"crossref","unstructured":"Birnbaumer L, Perez-Reyes E, Bertrand P, Gudermann T, Wei XY, Kim H, Castellano A, Codina J: Molecular diversity and function of G proteins and calcium channels. Biol Reprod 1991;44:207-224.10.1095\/biolreprod44.2.2071849023","DOI":"10.1095\/biolreprod44.2.207"},{"key":"2026070713070507400_ref35","doi-asserted-by":"crossref","unstructured":"Gompf HS, Greenberg JH, Aston-Jones G, Ianculescu AG, Scanlan TS, Dratman MB: 3-Monoiodothyronamine: the rationale for its action as an endogenous adrenergic-blocking neuromodulator. Brain Res 2010;1351:130-140.10.1016\/j.brainres.2010.06.06720615397","DOI":"10.1016\/j.brainres.2010.06.067"}],"container-title":["European Thyroid Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/381801","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.bioscientifica.com\/etj\/article-pdf\/4\/1_Suppl\/21\/35689\/etj381801.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/etj\/article-pdf\/4\/1_Suppl\/21\/35689\/etj381801.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T17:44:25Z","timestamp":1783446265000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.bioscientifica.com\/etj\/article\/4\/1_Suppl\/21\/4868\/The-Multitarget-Ligand-3-Iodothyronamine-Modulates"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,5,29]]},"references-count":35,"journal-issue":{"issue":"1_Suppl","published-print":{"date-parts":[[2015,9,1]]}},"URL":"https:\/\/doi.org\/10.1159\/000381801","relation":{},"ISSN":["2235-0802","2235-0640"],"issn-type":[{"value":"2235-0802","type":"electronic"},{"value":"2235-0640","type":"print"}],"subject":[],"published":{"date-parts":[[2015,5,29]]}}}