GABA-B . mGlu . Dopamine . Trace Amine . G-protein Coupled Receptors . GPCR

Deconstructing and reconstructing signaling complexes Dopamine Receptors Molecular In collaboration with B. Fakler (Freiburg iBr.) and C. Lüscher (Geneva) we have Connection to Clinical Practice of G-protein coupled receptors in the nervous system been awarded a Sinergia grant from the Swiss National Science Foundation to identify -associated proteins. We are analyzing several recep- Luigi Mariani, Raphael Gutzman, Neurobiology The signaling repertoire of G-protein coupled receptors (GPCRs) in the central ner- tor-associated proteins for their effects on dopamine receptor functions in vitro Stephan Frank vous system is expanded through interaction with trafficking, effector and regula- and in vivo. University Hospital Basel tory proteins that constitute stable multi-protein receptor complexes with distinct Synaptic composition and localization. We have started to deconstruct and reconstruct Trace Amine Receptor 1 Neural Stem Cells and Notch Signaling GPCR complexes in native and recombinant expression systems to address how In collaboration with M. Höhner (Roche, Basel) we have found that TAAR1 activa- in Brain Tumors the composition of such complexes influences fundamental processes such as tion silences GSK3ћ signaling of TAAR1/dopamine D2 receptor complexes (Har- We collaborated with M. Sailer and R. Gutzmann Plasticity neuronal excitability and network oscillations. Our ultimate goal is to identify novel meier et al., European Neuropsychopharmacol., 2015). Given that patients with on a neural stem cell culture model that can be drug targets for the treatment of neurological and psychiatric diseases. schizophrenia or bipolar disorder exhibit increased GSK3ћ signaling, TAAR1 de- used to investigate the epithelial to mesenchymal serves consideration as a target for the treatment of psychiatric disorders. transition (Sailer et al., Jove, 2016). We further col-

GABAB receptors laborated with V. Taylor, L. Mariani , S. Frank on a

GABAB receptors are the GPCRs for the inhibitory ќ-aminobutyric tumor suppressor function for Notch signaling in

acid (GABA). GABAB receptors have been implicated in a variety of neurological brain tumors (Giacchino et al., Cancer Cell, 2015). and psychiatric conditions, including , essential tremor, anxiety, depres- sion, schizophrenia, bipolar disorder, addiction and pain. Despite the involvement

of GABAB receptors in mental health disorders, the clinical use of GABAB recep- Bernhard Bettler tor drugs is currently limited to agonists and the treatment of narcolepsy, neuro- Selected Publications Department of Biomedicine pathic pain, spasticity and dystonia. One reason for this is that the main therapeu- Pin J-P, Bettler B. (2016). Organization and functions Physiology tic effect of – muscle relaxation – is an unwanted side effect for mental of mGlu and GABAB receptor complexes. Nature University of Basel health indications. 540(7631), 60–68 Schwenk J, Pérez-Garci E, Schneider A, Kollewe A, Gauth- A large body of work supports that native GABAB receptors vary in their kinetic ier-Kemper A, Fritzius T, Raveh A, Dinamarca MC Ha- and signaling properties. To some extent, this may be explained by receptor-as- nuschkin A, Bildl W et al. (2016) Modular composition sociated proteins. In collaboration with B. Fakler (Freiburg iBr) we purified native and dynamics of native GABAB receptor complexes identified by high-resolution proteomics. Nature Neu- GABAB receptor complexes and identified ~30 constituents using tandem mass- rosci. 19(2), 233–42 spectrometry (Schwenk et al., Nature Neurosci., 2016). We found that GABA re- B Zhang J, Tan L, Ren Y, Liang J, Lin R, Feng Q, Zhou J, Hu F, ceptors not only comprise principal GABAB1 and GABAB2 subunits but also four Ren J, Wie C, Yu T, et al. (2016). Presynaptic Excitation auxiliary KCTD subunits. These auxiliary subunits regulate the kinetics of the re- via GABAB Receptors in Habenula Cholinergic ceptor response and influence circadian rhythmicity and emotions in behaving Regulates Fear Memory Expression. Cell 166(3), 716- 28 Group Members Dr. Rostislav Turecek mice (Turecek et al., , 2014; Cathomen et al., Transl. Psychiatry, 2016). Prin- Turecek R, Schwenk J, Fritzius T, Ivankova K, Zolles G, (Postdoc) Lisa Adelfinger cipal and auxiliary receptors subunits, together with the heterotrimeric G-protein, Adelfinger L, Jacquier V, Besseyrias V, Gassmann M, Dr. Celine Ullrich (PhD Student)* can be viewed as the core building blocks of receptors. Peripheral building blocks Schulte U, et al. (2014) Auxiliary GABAB receptor sub- (Postdoc) David Berner units uncouple G-protein ћќ subunits from effector Dr. Daniel Ulrich can bind to these core building blocks and assemble into receptor complexes (PhD Student)* channels to induce desensitization. Neuron 82, 1032– (Postdoc) with unique properties. Peripheral building blocks comprise effector channels, el- Valérie Besseyrias 1044 Dr. Ruth Werthmann ements of the presynaptic release machinery and proteins that regulate recep- (Technician) Hanack C, Moroni M, Lima WC, Wende H, Kirchner M, (Postdoc)* Dr. Margarita Dinamarca tor localization. For example, we identified HCN channels (Schwenk et al., Nature Adelfinger L, Schrenk-Siemens K, Tappe-Theodor A, Dr. Xiaomo Wu Ceballos (Postdoc) Neurosci., 2016) and TRPV1 channels (Hanack et al., Cell, 2016; collaboration with Wetzel C, Kuich H, et al. (2015) GABA blocks patholog- (Postdoc) Ramona Felix ical but not acute TRPV1 pain signals. Cell 160(4), 759– J. Siemens, Heidelberg) as novel effector channels of GABAB receptors. Togeth- (Administrative Assistant) * left during report period 770 Dr. Thorsten Fritzius er with H. Bräuner-Osborne (Copenhagen), a medicinal chemist, we are currently (Postdoc) developing synthetic compounds that interfere with defined receptor complexes. Dr. Martin Gassmann These compounds will be tested for their therapeutic potential in psychiatric indi- (Research Associate) cations. The advantages of such compounds could include a reduction in side ef- Dr. Anja Harmeier (Postdoc)* fects as well as entirely new therapeutic applications. Fig. 1: Scheme depicting the functional consequences of the association of GABAB receptors and -/- Dr. Txomin Lalanne hyperpolarization-activated cyclic nucleotide-gated HCN2 channels in WT but not in KCTD16 dopaminergic neurons. Proximity of HCN2 channels and GABA receptors at the postsynapse of (Postdoc) mGlu5 Receptors B Dr. Alessandra Porcu GABAergic synapses in WT neurons facilitates activation of HCN2 channels by hyperpolarizing In collaboration with L. Lindemann (Roche, Basle) we have identified mGlu5 recep- + (Postdoc)* GABA-mediated IPSPs (induced by GABAB receptor-activated Kir3-type K channels and GABAA tor-associated proteins. We are currently characterizing the newly identified pro- - Dr. Adi Raveh Cl channels). Activated HCN2 channels introduce an additional shunt in the membrane that (Postdoc) teins for their effects on mGlu5 receptor functions in vitro and in vivo. interferes with propagation of IPSPs to the soma of dopaminergic neurons (indicated with a -/- Pascal Dominic Rem weak arrow). In KCTD16 neurons HCN2 channels are dissociated from receptors and their (PhD Student) effector Kir3 channels, which removes HCN2 channels from the hyperpolarizing influence of IP- Dr. Yanwei Tan SPs. A drift of the HCN2 channels to more distal dendritic locations, relative to the postsynapse, (Postdoc) results in stronger signal propagation and larger IPSPs at the soma (indicated with a strong arrow). Adapted from Schwenk et al., Nature Neurosci. 19, 2016.

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