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Basic Thyroidology / Original Paper

Free Access

The Multitarget Ligand 3-Iodothyronamine Modulates β-Adrenergic Receptor 2 Signaling

Dinter J.a · Khajavi N.b · Mühlhaus J.a · Wienchol C.L.a · Cöster M.d · Hermsdorf T.d · Stäubert C.d · Köhrle J.c · Schöneberg T.d · Kleinau G.a · Mergler S.b · Biebermann H.a

Author affiliations

aInstitut für Experimentelle Pädiatrische Endokrinologie, bDepartment of Ophthalmology, and cInstitut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin, Berlin, and dInstitut für Biochemie, Molekulare Biochemie, Medizinische Fakultät, University of Leipzig, Leipzig, Germany

Corresponding Author

Heike Biebermann

Institut für Experimentelle Pädiatrische Endokrinologie

Charité-Universitätsmedizin Berlin, Augustenburger Platz 1

DE-13353 Berlin (Germany)

E-Mail heike.biebermann@charite.de

Stefan Mergler

Department of Ophthalmology, Charité-Universitätsmedizin Berlin

Augustenburger Platz 1

DE-13353 Berlin (Germany)

E-Mail Stefan.Mergler@charite.de

Related Articles for ""

Eur Thyroid J 2015;4(suppl 1):21-29

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Background: 3-Iodothyronamine (3-T1AM), a signaling molecule with structural similarities to thyroid hormones, induces numerous physiological responses including reversible body temperature decline. One target of 3-T1AM 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-T1AM remain detectable in TAAR1 knockout mice, suggesting further targets for 3-T1AM such as adrenergic receptors. Therefore, we evaluated whether β-adrenergic receptor 1 (ADRB1) and 2 (ADRB2) signaling is affected by 3-T1AM 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-T1AM-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 Ca2+ imaging was utilized to delineate 3-T1AM-induced Ca2+ signaling. Results: 3-T1AM (10-5- 10-10M) enhanced isoprenaline-induced ADRB2-mediated Gs signaling but not that of ADRB1-mediated signaling. MAPK signaling remained unaffected for both receptors. In IOBA-NHC cells, norepinephrine-induced Ca2+ influxes were blocked by the nonselective ADRB blocker timolol (10 µM), indicating that ADRBs are most likely linked with Ca2+ channels. Notably, timolol was also found to block 3-T1AM (10-5M)-induced Ca2+ influx. Conclusions: The presented data support that 3-T1AM directly modulates β-adrenergic receptor signaling. The relationship between 3-T1AM and β-adrenergic signaling also reveals a potential therapeutic value for suppressing Ca2+ channel-mediated inflammation processes, occurring in eye diseases such as conjunctivitis.

© 2015 European Thyroid Association Published by S. Karger AG, Basel


  1. Scanlan TS: Minireview: 3-iodothyronamine (T1AM): a new player on the thyroid endocrine team? Endocrinology 2009;150:1108-1111.
  2. Zucchi R, Accorroni A, Chiellini G: Update on 3-iodothyronamine and its neurological and metabolic actions. Front Physiol 2014;5:402.
  3. Piehl S, Hoefig CS, Scanlan TS, Kohrle J: Thyronamines - past, present, and future. Endocr Rev 2011;32:64-80.
  4. 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.
  5. Cody V, Meyer T, Dohler KD, Hesch RD, Rokos H, Marko M: Molecular structure and biochemical activity of 3,5,3′-triiodothyronamine. Endocr Res 1984;10:91-99.
  6. 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.
  7. 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.
  8. 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.
  9. 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. 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.
  11. 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.
  12. Khajavi N, Reinach PS, Skrzypski M, Lude A, Mergler S: L-Carnitine reduces in human conjunctival epithelial cells hypertonic-induced shrinkage through interacting with TRPV1 channels. Cell Physiol Biochem 2014;34:790-803.
    External Resources
  13. Matsuo T, Cynader MS: Localization of α2- adrenergic receptors in the human eye. Ophthalmic Res 1992;24:213-219.
  14. 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.
  15. Neufeld AH, Zawistowski KA, Page ED, Bromberg BB: Influences on the density of β-adrenergic receptors in the cornea and iris - ciliary body of the rabbit. Invest Ophthalmol Vis Sci 1978;17:1069-1075.
    External Resources
  16. Mühlhaus J, Dinter J, Nürnberg D, Rehders M, Depke M, Golchert J, Homuth G, Yi CX, Morin S, Köhrle 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.
  17. 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.
  18. Schröder R, Janssen N, Schmidt J, Kebig A, Merten N, Hennen S, Müller A, Blättermann S, Mohr-Andrä 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.
  19. Piechowski CL, Rediger A, Lagemann C, Mühlhaus J, Muller A, Pratzka J, Tarnow P, Grüters 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.
  20. Grynkiewicz G, Poenie M, Tsien RY: A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 1985;260:3440-3450.
    External Resources
  21. Frielle T, Daniel KW, Caron MG, Lefkowitz RJ: Structural basis of β-adrenergic receptor subtype specificity studied with chimeric β12-adrenergic receptors. Proc Natl Acad Sci USA 1988;85:9494-9498.
  22. 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.
  23. 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.
  24. Regard JB, Sato IT, Coughlin SR: Anatomical profiling of G protein-coupled receptor expression. Cell 2008;135:561-571.
  25. 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.
  26. Smith NJ, Milligan G: Allostery at G protein-coupled receptor homo- and heteromers: uncharted pharmacological landscapes. Pharmacol Rev 2010;62:701-725.
  27. Sartania N, Appelbe S, Pediani JD, Milligan G: Agonist occupancy of a single monomeric element is sufficient to cause internalization of the dimeric β2-adrenoceptor. Cell Signal 2007;19:1928-1938.
  28. 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.
  29. Thor D, Schulz A, Hermsdorf T, Schöneberg T: Generation of an agonistic binding site for blockers of the M3 muscarinic acetylcholine receptor. Biochem J 2008;412:103-112.
  30. Baker JG, Hill SJ: Multiple GPCR conformations and signalling pathways: implications for antagonist affinity estimates. Trends Pharmacol Sci 2007;28:374-381.
  31. Wenzel-Seifert K, Seifert R: Molecular analysis of β2-adrenoceptor coupling to Gs-, Gi-, and Gq-proteins. Mol Pharmacol 2000;58:954-966.
    External Resources
  32. 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.
  33. 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.
  34. 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.
  35. 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.

Article / Publication Details

First-Page Preview
Abstract of Basic Thyroidology / Original Paper

Received: November 17, 2014
Accepted: March 19, 2015
Published online: May 29, 2015
Issue release date: September 2015

Number of Print Pages: 9
Number of Figures: 4
Number of Tables: 0

ISSN: 2235-0640 (Print)
eISSN: 2235-0802 (Online)

For additional information: https://www.karger.com/ETJ

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