A06

A06 Project Movie

A06

In the 1st funding period project A06 profiled uncharacterized cAMP-regulating proteins in T cells. Their focus was on the orphan GPCR, GPR52, and PDE2A. GPR52 has been described to be involved in neuropsychiatric disorders, while its role in T cell physiology has not been explored. Project A06 set out to elucidate the impact of GPR52 in the generation of cAMP levels in T cells and its contribution to T cell physiology and Treg-mediated immunosuppression. Upon treatment with the selective GPR52 agonist FTBMT (4-(3-(3-fluoro-5-(trifluoromethyl)benzyl)-5-methyl-1H-1,2,4-triazol-1-yl)-2-methylbenzamide), non-activated Treg showed a significantly higher cAMP response in comparison to Tcon, whereas in activated T cells a diminished difference between the two T cell subsets upon GPR52 agonist stimuli was observed. However, GPR52 knockout T cells showed no difference in T cell function, and no effect in the EAE model was detected when comparing GPR52 knockout mice to wildtype littermates. By contrast, inhibition of PDE2A significantly suppressed Th1 differentiation, but did not alter Th2, Th17 or Treg differentiation, while at the same time stimulated Tcon cell activation. Further, cGMP generation by atrial natriuretic peptide (ANP) resulted in decreased cAMP levels in activated Tcon in comparison to non-activated T cells, possibly due to upregulated PDE2A. Furthermore, ANP led to an increase in the expression of early activation marker CD25 and CD69 after CD3/CD28 stimulation. Also, project A06 showed that close proximity of non-activated Treg resulted in an increase of cAMP in activated Tcon. This process was blocked by inhibitors of gap junctions, indicating a direct transfer of cAMP from to Treg to Tcon.

Prof. Dr. Viacheslav O. Nikolaev

Selected publications (*equal contribution)

 

  1. Berisha F, Götz K, Wegener JW, Brandenburg S, Subramanian H, Molina CE, Rueffer A, Petersen J, Bernhardt A, Girdauskas E, Jungen C, Pape U, Kraft AE, Warnke S, Lindner D, Westermann D, Blankenberg S, Meyer C, Hasenfuß G, Lehnart SE, Nikolaev VO (2021) cAMP Imaging at Ryanodine Receptors Reveals β2-Adrenoceptor Driven Arrhythmias. Circ Res 129(1):81-94
  2. Subramanian H, Froese A, Jönsson P, Schmidt H, Gorelik J, Nikolaev VO (2021) Distinct submembrane localisation compartmentalises cardiac NPR1 and NPR2 signalling to cGMP. Nature Commun 9:2446
  3. Sprenger JU, Perera RK, Steinbrecher JH, Lehnart SE, Maier LS, Hasenfuss G, Nikolaev VO (2015) In vivo model with targeted cAMP biosensor reveals changes in receptor-microdomain communication in cardiac disease. Nature Commun 6:6965.
  4. Perera RK, Sprenger JU, Steinbrecher JH, Hübscher D, Lehnart SE, Abesser M, Schuh K, ElArmouche A, Nikolaev VO (2015) Microdomain switch of cGMP-regulated phosphodiesterases leads to ANP-Induced augmentation of beta-adrenoceptor-stimulated contractility in early cardiac hypertrophy. Circ Res 116:1304-1311.
  5. Götz KR, Sprenger JU, Perera RK, Steinbrecher JH, Lehnart SE, Kuhn M, Gorelik J, Balligand JL, Nikolaev VO (2014) Transgenic mice for real-time visualization of cGMP in intact adult cardiomyocytes. Circ Res 114:1235-1245.
  6. Börner S, Schwede F, Schlipp A, Berisha F, Calebiro D, Lohse MJ, Nikolaev VO (2011) FRET measurements of intracellular cAMP concentrations and cAMP analog permeability in intact cells. Nature Protoc 6:427-438.
  7. Nikolaev VO, Moshkov A, Lyon AR, Miragoli M, Novak P, Paur H, Lohse MJ, Korchev YE, Harding SE, Gorelik J. (2010) Beta2-adrenergic receptor redistribution in heart failure changes cAMP compartmentation. Science 327:1653-1657.
  8. Calebiro D*, Nikolaev VO*, Gagliani MC, de Filippis T, Dees C, Tacchetti C, Persani L, Lohse MJ (2009) Persistent cAMP-signals triggered by internalized G-protein-coupled receptors. PLoS Biol 7:e1000172.
  9. Nikolaev VO, Boivin V, Stork S, Angermann CE, Ertl G, Lohse MJ, Jahns R (2007) A novel fluorescence method for the rapid detection of functional β1-adrenergic receptor autoantibodies in heart failure. J Am Coll Cardiol 50:423-431.
  10. Nikolaev VO, Gambaryan S, Lohse MJ (2006) Fluorescent sensors for rapid monitoring of intracellular cGMP. Nature Methods 3, 23-25. 

 

 

 

 

Prof. Dr. Manuel Alexander Friese

Selected publications (*equal contribution)

 

  1. Woo MS, Ufer F, Rothammer N, Di Liberto G, Binkle L, Haferkamp U, Sonner JK, Engler JB, Hornig S, Bauer S, Wagner I, Egervari K, Raber J, Duvoisin RM, Pless O, Merkler D, Friese MA (2021) Neuronal metabotropic glutamate receptor 8 protects against neurodegeneration in CNS inflammation. J Exp Med 3;218(5):e20201290.
  2. Kaufmann M, Evans H, Schaupp AL, Engler JB, Kaur G, Willing A, Kursawe N, Schubert C, Attfield KE, Fugger L, Friese MA (2021) Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis. Med 12;2(3):296-312.e8.
  3. Rosenkranz SC, Shaposhnykov AA, Träger S, Engler JB, Witte ME, Roth V, Vieira V, Paauw N, Bauer S, Schwencke-Westphal C, Schubert C, Bal LC, Schattling B, Pless O, van Horssen J, Freichel M, Friese MA (2021) Enhancing mitochondrial activity in neurons protects against neurodegeneration in a mouse model of multiple sclerosis. Elife 10:e61798.
  4. Schattling B, Engler JB, Volkmann C, Rothammer N, Woo MS, Petersen M, Winkler I, Kaufmann M, Rosenkranz SC, Fejtova A, Thomas U, Bose A, Bauer S, Träger S, Miller KK, Brück W, Duncan KE, Salinas G, Soba P, Gundelfinger ED, Merkler D, Friese MA (2019) Bassoon proteinopathy drives neurodegeneration in multiple sclerosis. Nat Neurosci 22(6):887-896.
  5. Engler JB, Kursawe N, Solano ME, Patas K, Wehrmann S, Heckmann N, Lühder F, Reichardt HM, Arck PC, Gold SM, Friese MA (2017) Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy. Proc Natl Acad Sci USA 114:E181-E190.
  6. Ufer F, Vargas P, Engler JB, Tintelnot J, Schattling B, Winkler H, Bauer S, Kursawe N, Willing A, Keminer O, Ohana O, Salinas-Riester G, Pless O, Kuhl D, Friese MA (2016) Arc/Arg3.1 governs inflammatory dendritic cell migration from the skin and thereby controls T cell activation. Sci Immunol 1:eaaf8665.
  7. Schattling B, Steinbach K, Thies E, Kruse M, Menigoz A, Ufer F, Flockerzi V, Brück W, Pongs O, Vennekens R, Kneussel M, Freichel M, Merkler D, Friese MA (2012) TRPM4 cation channel mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat Med 1805-1811.
  8. Friese MA, Jakobsen KB, Friis L, Etzensperger R, Craner MJ, McMahon RM, Jensen LT, Huygelen V, Jones EY, Bell JI, Fugger L (2008) Opposing effects of HLA class I molecules in tuning autoreactive CD8+ T cells in multiple sclerosis. Nat Med 11:1227-1235.
  9. Tzartos JS*, Friese MA*, Craner MJ, Palace J, Newcombe J, Esiri MM, Fugger L (2008) Interleukin17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol 172:146-155. 
  10. Friese MA, Craner MJ, Etzensperger R, Vergo S, Wemmie JA, Welsh MJ, Vincent A, Fugger (2007) L. Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nature Med 1483-1489.

Our Team

Prof. Dr. Viacheslav Nikolaev

Dept. of Experimental Cardiovascular Research

University Medical Centre Hamburg-Eppendorf (UKE)

Prof. Dr. Manuel Friese

Institute of Neuroimmunology and Multiple Sclerosis (INIMS)

Center for Molecular Neurobiology Hamburg (ZMNH)

M.Sc. Roberta Kurelic

Dept. of Experimental Cardiovascular Research

University Medical Centre Hamburg-Eppendorf (UKE)

Contact

University Medical Center Hamburg-Eppendorf 
Department of Biochemistry and Molecular Cell Biology 
Martinistrasse 52
20246 Hamburg

Scientific Coordinator

Dr. Björn-Philipp Diercks
Fon: +49  (0) 40 7410 54338
E-Mail: b.diercks©uke.de

Administration

Laura Mitsching
Fon: +49  (0) 40 7410 50301
E-Mail: l.mitsching©uke.de