Neuronal Signalling Pathways

Group leader

Michael Courtney, Ph.D.
michael.courtney [at] btk.fi , miccou [at] utu.fi

Contact Information

Neuronal Signalling Laboratory
Turku Centre for Biotechnology
University of Turku
Biocity
P.O. Box 123
Tykistökatu 6
FIN-20521 Turku,  Finland
+358 (0)2 333 8567

News

The programme for the upcoming 2nd National High-Content Analysis and High-Throughput Microscopy Workshop, on 19-20 June 2017, Turku, Finland is now live at this link Register by the deadline of 8th June at this link

12th May 2017: Our latest paper is out at www.nature.com/articles/ncomms15017

Description of the Research

Stress-activated signalling pathways are widely accepted to play a significant role in disease progression in and outside the nervous system. However, earlier work indicates that generic mediators of these pathways such as c-Jun N-terminal kinases/p38 MAP kinases also contribute to development, differentiation, plasticity, and even cell survival and proliferation. This suggests that direct inhibition of these mediators may be of only limited therapeutic use. Moreover, our recent work has shown that, in some cases, the downstream functional consequences of pathway inhibition can depend far more on the frequency of inhibition than on the total integrated inhibition applied. This unexpected result is likely to be a consequence of cell signalling circuit resonance. In order to exploit these pathways for the development of novel drugs for neuronal and other disorders, it will be necessary to elucidate the mechanisms that organise these pathways into pools with pathological or physiological actions within the complex structure of cell such as neurons.

Our laboratory investigates protein interactions underlying signalling in cells, with particular emphasis placed on responses to the impact of cell stress signalling on physiological and pathological pathways and the mechanisms that cells use to organise signalling proteins thereby ensuring specificity of function and efficiency of signal propagation. Our research combines biochemical and biophysical studies of key proteins together with cell and molecular biology including protein engineering, single-cell and population-based optical measurements and optical actuation approaches. This work is  complemented by assay development and high-throughput methods aimed at identification of small molecule active on pathways under study. We complement these approaches by collaboration with teams focusing on preclinical models of disease, structural biology and mathematical modelling of signalling networks and circuits.

Research Areas

Organisation of Signalling Pathways – Roles in Disorders of the Nervous System

    • NOS1AP/CAPON: mechanisms of action on NMDA receptor signalling through nNOS

An Optogenetic and Optopharmacological toolbox for precise control of cell signalling pathways

    • A novel design strategy for rapid generation of optically regulated inhibitors
    • OptoJNKi and Optop38i, new tools for precise spatiotemporal control of JNK and p38 pathways reference, press release

Development of High-Content Analysis and High-Throughput Microscopy methods

Link to our HCA / HTM Facility Page (under development)

Group Members

PI: Michael Courtney

Postgraduate Students:

    • Arkadiusz Popinigis
    • Lili Li
    • Lorenzo Li Greci
    • Catarina Seidi
    • Xijun Wang
    • Elena Goltseva (co-supervision with Peter James, University of Lund)

 

Undergraduate Students:

    • Ghada Bani Younes

 

Visiting Researchers:

    • Esin Candemir (Frankfurt University Hospital)

Major Collaborations

  • Andrea Hohmann and Yvonne Lai, University of Indiana, Bloomington, USA
  • Florian Freudenberg, Frankfurt University Hospital, Frankfurt, Germany
  • Nael Nadif Kasri, Donders Institute for Brain, Radboud University Medical Center, Nijmegen, Netherlands
  • Jari Koistinaho, University of Eastern Finland, Kuopio
  • Antti Poso, University of Eastern Finland, Kuopio
  • Janne Jänis, University of Eastern Finland, Joensuu
  • Tassos Papageorgiou, Turku Centre for Biotechnology, Turku
  • Laura Elo, Turku Centre for Biotechnology, Turku

Project Funding

NIH – NCI

  • NOS1AP as a novel target for treating pathological pain

TEKES – Finnish Funding Agency for Innovation

  • New knowledge and business from research ideas programme

EU FP7

  • MSCA – Initial Training Network – r’BIRTH

Academy of Finland

  • Targeting schizophrenia-related phenotypes using small molecules directed against NOS1AP

The Magnus Ehrnrooth Foundation

Selected References

2017

Melero-Fernandez de Mera RM*, Li LL*, Popinigis A, Cisek K, Tuittila M, Yadav L, Serva A, Courtney MJ (2017) A simple optogenetic MAPK inhibitor design reveals resonance between transcription-regulating circuitry and temporally-encoded inputs. (*equal contribution) Nat. Commun. 8, 15017.
doi: 10.1038/ncomms15017. PMID: 28497795. press release

Li LL, Cisek K, Courtney MJ (2017) Efficient Binding of the NOS1AP C-Terminus to the nNOS PDZ Pocket Requires the Concerted Action of the PDZ Ligand Motif, the Internal ExF Site and Structural Integrity of an Independent Element. Front. Mol. Neurosci. 10:58.
doi: 10.3389/fnmol.2017.00058. PMID: 28360833.

von Ossowski L, Li LL, Möykkynen T, Coleman SK, Courtney MJ, Keinänen K. (2017) Cysteine 893 is a target of regulatory thiol modifications of GluA1 AMPA receptors. PLoS One. Feb 2;12(2):e0171489.
doi: 10.1371/journal.pone.0171489. PMID: 28152104.

2016

Kamiya T, Courtney M, Laukkanen MO (2016) Redox-Activated Signal Transduction Pathways Mediating Cellular Functions in Inflammation, Differentiation, Degeneration, Transformation, and Death. Oxid Med Cell Longev. 2016:8479718.
doi: 10.1155/2016/8479718. PubMed PMID: 28101299

Lehtonen S, Jaronen M, Vehviläinen P, Lakso M, Rudgalvyte M, Keksa-Goldsteine V, Wong G, Courtney MJ, Koistinaho J, Goldsteins G (2016) Inhibition of excessive oxidative protein folding is protective in MPP+ toxicity-induced PD models. Antioxidants & Redox Signaling. 25(8): 485-497.
doi: 10.1089/ars.2015.6402. PMID: 27139804.

Ba W, Selten MM, van der Raadt J, van Veen H, Li LL, Benevento M, Oudakker AR, Lasabuda RS, Letteboer SJ, Roepman R, van Wezel RJ, Courtney MJ, van Bokhoven H, Nadif Kasri N (2016) ARHGAP12 Functions as a Developmental Brake on Excitatory Synapse Function. Cell Rep. 14, 1355-1368.
doi: 10.1016/j.celrep.2016.01.037 PMID: 26854232

2015

Li LL, Melero-Fernandez de Mera RM, Chen J, Ba W, Nadif Kasri N, Zhang M, Courtney MJ (2015) Unexpected Heterodivalent Recruitment of NOS1AP to nNOS Reveals Multiple Sites for Pharmacological Intervention in Neuronal Disease Models. J Neurosci. 35, 7349-7364.
doi: 10.1523/JNEUROSCI.0037-15.2015 PMID: 25972165 press release

2014

Courtney MJ, Li LL, Lai YY (2014) Mechanisms of NOS1AP action on NMDA receptor-nNOS signalling. Front Cell Neurosci. 8:252.
doi:  10.3389/fncel.2014.00252 PMID: 25221472

Tortoriello G, Morris C, Alpar A, Fuzik J, Shirran SL, Calvigione D, Keimpema E, Botting CH, Reinecke K, Herdegen T, Courtney M, Hurd YL, Harkany T (2014) Miswiring the brain: Δ9-tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin-2 degradation pathway. EMBO J. 33:668-85.
doi:  10.1002/embj.201386035 PMID: 24469251

2013

Li LL, Ginet V, Liu X, Vergun O, Tuittila M, Mathieu M, Bonny C, Puyal J, Truttmann AC, Courtney MJ (2013) The nNOS-p38MAPK pathway is mediated by NOS1AP during neuronal death. J Neurosci. 33, 8185-8201.
doi: 10.1523/JNEUROSCI.4578-12.2013 PMID: 23658158 press release

2012

D’Orsi B, Bonner H, Tuffy LP, Düssmann H, Woods I, Courtney MJ, Ward MW, Prehn JH (2012) Calpains Are Downstream Effectors of bax-Dependent Excitotoxic Apoptosis. J Neurosci. 32, 1847-1858.
doi: 10.1523/JNEUROSCI.2345-11.2012. PMID: 22302823

Björkblom B, Padzik A, Mohammad H, Westerlund N, Komulainen E, Hollos P, Parviainen L, Papageorgiou AC, Iljin K, Kallioniemi O, Kallajoki M, Courtney MJ, Mågård M, James P, Coffey ET (2012) JNK phosphorylation of marcksl1 determines actin stability and migration in neurons and in cancer cells. Mol Cell Biol. 32, 3513-26. PMID: 22751924

Yang H, Courtney MJ, Martinsson P, Manahan-Vaughan D (2011) Hippocampal long-term depression is enhanced, depotentiation is inhibited and long-term potentiation is unaffected by the application of a selective c-Jun N-terminal kinase inhibitor to freely behaving rats. Eur J Neurosci. 33, 1647-1655.
doi: 10.1111/j.1460-9568.2011.07661.x. PMID: 21453290

Westerlund N, Zdrojewska J, Padzik A, Komulainen E, Björkblom B, Rannikko E, Tararuk T, Garcia-Frigola C, Sandholm J, Nguyen L, Kallunki T, Courtney MJ and Coffey E.T. (2011) Phosphorylation of SCG10/stathmin-2 determines multipolar stage exit and neuronal migration rate. Nat Neurosci. 14, 305-313. PMID: 21297631

Hellwig CT, Kohler BF, Lehtivarjo AK, Dussmann H, Courtney MJ, Prehn JH, Rehm M. Real time analysis of tumor necrosis factor-related apoptosis-inducing ligand/cycloheximide-induced caspase activities during apoptosis initiation. J Biol Chem. 2008 Aug 1;283(31):21676-85. PMID: 18522940

Björkblom B, Vainio JC, Hongisto V, Herdegen T, Courtney MJ*, Coffey ET*. All JNKs can kill, but nuclear localization is critical for neuronal death. (*equal contribution) J Biol Chem. 2008 Jul 11;283(28):19704-13. PMID: 18474608

Hongisto V, Vainio JC, Thompson R, Courtney MJ, Coffey ET. The Wnt pool of glycogen synthase kinase 3beta is critical for trophic-deprivation-induced neuronal death. Mol Cell Biol. 2008 Mar;28(5):1515-27. PMID: 18195042

Semenova MM*, Mäki-Hokkonen AM*, Cao J*, Komarovski V, Forsberg KM, Koistinaho M, Coffey ET, Courtney MJ. Rho mediates calcium-dependent activation of p38alpha and subsequent excitotoxic cell death. (*equal contribution) Nat Neurosci. 2007 Apr;10(4):436-43. PMID: 17369826

Tararuk T, Ostman N, Li W, Björkblom B, Padzik A, Zdrojewska J, Hongisto V, Herdegen T, Konopka W, Courtney MJ, Coffey ET. JNK1 phosphorylation of SCG10 determines microtubule dynamics and axodendritic length. J Cell Biol. 2006 Apr 24;173(2):265-77. PMID: 16618812

Cao J, Viholainen JI, Dart C, Warwick HK, Leyland ML, Courtney MJ. The PSD95-nNOS interface: a target for inhibition of excitotoxic p38 stress-activated protein kinase activation and cell death. J Cell Biol. 2005 Jan 3;168(1):117-26. PMID: 15631993

Björkblom B, Ostman N, Hongisto V, Komarovski V, Filén JJ, Nyman TA, Kallunki T, Courtney MJ, Coffey ET. Constitutively active cytoplasmic c-Jun N-terminal kinase 1 is a dominant regulator of dendritic architecture: role of microtubule-associated protein 2 as an effector. J Neurosci. 2005 Jul 6;25(27):6350-61. PMID: 16000625

Cao J, Semenova MM, Solovyan VT, Han J, Coffey ET, Courtney MJ. Distinct requirements for p38alpha and c-Jun N-terminal kinase stress-activated protein kinases in different forms of apoptotic neuronal death. J Biol Chem. 2004 Aug 20;279(34):35903-13. PMID: 15192112

Hongisto V, Smeds N, Brecht S, Herdegen T, Courtney MJ, Coffey ET. Lithium blocks the c-Jun stress response and protects neurons via its action on glycogen synthase kinase 3.Mol Cell Biol. 2003 Sep;23(17):6027-36. PMID: 12917327

Coffey ET, Smiciene G, Hongisto V, Cao J, Brecht S, Herdegen T, Courtney MJ. c-Jun N-terminal protein kinase (JNK) 2/3 is specifically activated by stress, mediating c-Jun activation, in the presence of constitutive JNK1 activity in cerebellar neurons. J Neurosci. 2002 Jun 1;22(11):4335-45. PMID: 12040039

Solovyan VT, Bezvenyuk ZA, Salminen A, Austin CA, Courtney MJ. The role of topoisomerase II in the excision of DNA loop domains during apoptosis. J Biol Chem. 2002 Jun 14;277(24):21458-67. PMID: 11940566

Coffey ET, Hongisto V, Dickens M, Davis RJ, Courtney MJ. Dual roles for c-Jun N-terminal kinase in developmental and stress responses in cerebellar granule neurons. J Neurosci. 2000 Oct 15;20(20):7602-13. PMID: 11027220

Courtney MJ, Coffey ET. The mechanism of Ara-C-induced apoptosis of differentiating cerebellar granule neurons. Eur J Neurosci. 1999 Mar;11(3):1073-84. PMID: 10103100

Courtney MJ, Akerman KE, Coffey ET. Neurotrophins protect cultured cerebellar granule neurons against the early phase of cell death by a two-component mechanism. J Neurosci. 1997 Jun 1;17(11):4201-11. PMID: 9151737