Neuronal Signalling Pathways
Michael Courtney, Ph.D.
michael.courtney [at] btk.fi , miccou [at] utu.fi
Neuronal Signalling Laboratory
Turku Centre for Biotechnology
University of Turku
P.O. Box 123
FIN-20521 Turku, Finland
+358 (0)50 464 9827
Description of Research
Aberrant signalling is widely accepted to play a significant role in the initiation and progression of disease. However, disease-associated signalling pathways typically play important roles in development and physiology, complicating the use of drugs targeting signalling proteins. Thus, generic mediators such as the MAP kinases contribute to development, differentiation, plasticity, survival and proliferation in addition to their well-established roles in diseases. This suggests that direct inhibition of the MAPKs themselves may be of only limited therapeutic use. Our recent work has shown that the downstream functional consequences of pathway inhibition can depend more on the frequency of inhibition than on the total integrated inhibition applied. This is an unexpected result and is likely to relate to the resonant properties of cell signalling circuits, a currently poorly understood and largely overlooked phenomenon. In order to exploit signalling pathways for the generation of novel therapeutic approaches for disorders of the nervous system and other organs, it will be necessary to only fully elucidate the mechanisms that organise these pathways into pools with pathological or physiological actions within the complex structure of cells such as neurons, but also to acquire a better understanding of cell signalling dynamics.
Our laboratory investigates protein interactions shaping signalling dynamics in cells, with particular emphasis placed on 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 approaches including protein engineering, single-cell and population-based optical measurements together with design and development of optical and other actuation approaches and techniques. This work is complemented by assay development, high-throughput methods aimed at identification of small molecules 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.
Organisation of Signalling Pathways – Roles in Disorders of the Nervous System
An Optogenetic and Optopharmacological toolbox for precise control of cell signalling pathways
Development of High-Content Analysis and High-Throughput Microscopy tools and methods
- Applications for signalling pathways and neuroscience
- Workshops: check back later for the next workshop (last workshop was 19-20 June 2017 )
- provision of high-throughput infrastructure and services for biological research, chemical biology and early-stage drug discovery (link to Screening Unit page)
PI: Michael Courtney
- Lili Li
Postgraduate Students and Project Researchers:
- Lorenzo Li Greci
- Jesse Mattson
- Sean Robinson
- Xijun Wang
- Elena Goltseva (co-supervision with Peter James, University of Lund)
- Uruj Sarwar Hussain
- Solmaz Bikas (Frankfurt University Hospital)
- Andrea Hohmann and Yvonne Lai, University of Indiana, Bloomington, USA
- Francisco Lopez-Picón, Turku PET Centre, University of Turku
- Florian Freudenberg, Frankfurt University Hospital, Frankfurt, Germany
- Laura Elo, Turku Centre for Biotechnology, University of Turku
- Jing Tang, Institute for Molecular Medicine Finland and Department of Maths and Statistics, University of Turku
- Nael Nadif Kasri, Donders Institute for Brain, Radboud University Medical Center, Nijmegen, Netherlands
- Tassos Papageorgiou, Turku Centre for Biotechnology, University of Turku
- Antti Poso, University of Eastern Finland, Kuopio
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
Academy of Finland
- Targeting schizophrenia-related phenotypes using small molecules directed against NOS1AP
The Magnus Ehrnrooth Foundation
Robinson S and Courtney MJ (2018) Spatial quantification of the synaptic activity phenotype across large populations of neurons with Markov random fields. Bioinformatics, Sep 15;34(18):3196-3204.
doi: 10.1093/bioinformatics/bty322. PMID: 29897415.
Lee WH, Carey LM, Li LL, Xu Z, Lai YY, Courtney MJ, Hohmann A. (2018) ZLc002, a putative small molecule inhibitor of nNOS interaction with NOS1AP, suppresses inflammatory nociception and chemotherapy-induced neuropathic pain and synergizes with paclitaxel to reduce tumor cell viability. Mol Pain. Aug 29:1744806918801224.
doi: 10.1177/1744806918801224. PubMed PMID: 30157705.
Lee WH, Li LL, Chawla A, Hudmon A, Lai YY, Courtney MJ, Hohmann AG. (2018) Disruption of nNOS-NOS1AP protein-protein interactions suppresses neuropathic pain in mice. Pain. May;159(5):849-863.
doi: 10.1097/j.pain.0000000000001152. PMID: 29319606. press release
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.
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
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
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
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 and earlier
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