P11 and G protein-coupled receptor function & pharmacology

P11

Involvement of p11 in the molecular modulation of different GPCRs:

Our studies have uncovered the role of p11 (S100A10, annexin II light chain, calpactin I light chain) in the etiology of depression and the mechanism of action of antidepressants, as well as stress and immune responses. p11 is a multifunctional protein that interacts with with 5-HT receptors, ion channels, enzymes and chromatin remodeling factors, and is critically involved in stress responses, depression-like behaviors and antidepressant actions. The level of p11 mRNA and protein is downregulated in the brain of depressed humans, suicide subjects and a mouse model of depression. In contrast, the level of p11 is increased by three classes of antidepressant agents, including SSRIs, TCA, and mGluR5 antagonist, as well as electroconvulsive therapy. p11 knockout mice exhibit depression-like behaviors, and p11 overexpressing mice show antidepressant-like behaviors.

We have also identified a role for p11 in Parkinson’s disease (PD). We found that p11 is important in L-DOPA treatment in a rodent model of PD.  L-DOPA potently up-regulates p11 in dopaminoceptive neurons, and p11 is implicated in both beneficial and adverse actions of L-DOPA in rodent models of PD. PD patients have reduced p11 levels in putamen, substantia nigra and cortex from PD patients. Leukocyte p11 levels are altered in PD patients in a cell type-specific manner and positively correlate with PD severity and depression symptomatology.

Our most recent study shows that p11 affects the initial release of the stress hormone cortisol in mice by modulating the activity of specific neurons in the hypothalamus. Through a completely different signaling pathway originating in the brainstem, p11 also affects the release of two other stress hormones, adrenaline and noradrenaline. In addition, mice with p11 deficiency react more strongly to stress, with a higher heart rate and more signs of anxiety, compared to mice with normal p11 levels.

We are currently studying the involvement of p11 in the molecular modulation of different GPCRs (modulation of membrane trafficking, intracellular signaling and the specific interaction motif) and how this interaction impacts stress reactivity, dopaminergic neurodegeneration, response to ketamine treatment, and in cytoskeleton and cell motility.

Selected publications:

P11 deficiency increases stress reactivity along with HPA axis and autonomic hyperresponsiveness. Sousa VC, Mantas I, Stroth N, Hager T, Pereira M, Jiang H, Jabre S, Paslawski W, Stiedl O, Svenningsson P. Mol Psychiatry. 2020 Oct 1. doi: 10.1038/s41380-020-00887-0. Epub ahead of print.

Modulation of Ion Channels and Receptors by p11 (S100A10). Seo JS, Svenningsson P. Trends Pharmacol Sci. 2020 Jul;41(7):487-497.

Alterations of p11 in brain tissue and peripheral blood leukocytes in Parkinson’s disease. Green H, Zhang X, Tiklova K, Volakakis N, Brodin L, Berg L, Greengard P, Perlmann T, Svenningsson P. Proc Natl Acad Sci U S A. 2017 Mar 7;114(10):2735-2740. doi: 10.1073/pnas.1621218114.  

p11 modulates L-DOPA therapeutic effects and dyskinesia via distinct cell types in experimental Parkinsonism. Schintu N, Zhang X, Alvarsson A, Marongiu R, Kaplitt MG, Greengard P, Svenningsson P. Proc Natl Acad Sci U S A. 2016 Feb 2;113(5):1429-34. doi: 10.1073/pnas.1524303113.  

p11 and its role in depression and therapeutic responses to antidepressants. Svenningsson P, Kim Y, Warner-Schmidt J, Oh YS, Greengard P. Nat Rev Neurosci. 2013 Oct;14(10):673-80. Review 

Alterations in 5-HT1B receptor function by p11 in depression-like states. Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M, Vaugeois JM, Nomikos GG, Greengard P. Science. 2006 Jan 6;311(5757):77-80.

Orphan GPCRs with neuronal functions 

Characterization of novel orphan GPCRs, including GPR37, GPR37L1 and GPR88: 

Brain enriched GPCRs are putative targets for many disorders. GPR37 and GPR37L1 have gathered prominent attention for their potential role in neurodegenerative disease and brain repair.  The interest on GPR37 biology was bolstered when it was described as a Parkin substrate. GPR37, also known as parkin associated endothelin-like receptor (Pael-R), has been suggested to be toxically accumulated in autosomal recessive PD. This genetic form of PD is caused by a mutation in Parkin and a subsequent accumulation of all Parkin substrates promoting its endoplasmic reticulum aggregation and stress, neurotoxicity and neuronal death.   Both GPR37 and GPR37L1 have been reported to be robustly expressed in glial cells, hinting at a potential role of these cell types in PD as well.  We are currently studying the use of GPR37 as a specific new biomarker for PD and characterizing the molecular pharmacology and function of GPR37 and GPR37L1 using both advanced cell and animal models.  

GPR88 is enriched in striatal medium spiny neurons. GPR88 inhibits the activity of striatal projection neurons and mice lacking GPR88 display hyperactivity. Future development of GPR88 antagonists may be beneficial against PD symptomatology.

Selected publications: 

Ecto-GPR37: a potential biomarker for Parkinson’s disease. Morató X, Garcia-Esparcia P, Argerich J, Llorens F, Zerr I, Paslawski W, Borràs E, Sabidó E, Petäjä-Repo UE, Fernández-Dueñas V, Ferrer I, Svenningsson P, Ciruela F. Transl Neurodegener. 2021 Feb 26;10(1):8. doi: 10.1186/s40035-021-00232-7.

Update on GPCR-based targets for the development of novel antidepressants. Mantas I, Saarinen M, Xu ZD, Svenningsson P. Mol Psychiatry. 2021 Feb 15. doi: 10.1038/s41380-021-01040-1. Epub ahead of print.

Genetic deletion of GPR88 enhances the locomotor response to L-DOPA in experimental parkinsonism while counteracting the induction of dyskinesia. Mantas I, Yang Y, Mannoury-la-Cour C, Millan MJ, Zhang X, Svenningsson P. Neuropharmacology. 2020 Jan 1;162:107829. doi: 10.1016/j.neuropharm.2019.107829.  

GPR37 and GPR37L1 differently interact with dopamine 2 receptors in live cells. Hertz E, Terenius L, Vukojević V, Svenningsson P. Neuropharmacology. 2019 Jul 1;152:51-57. doi: 10.1016/j.neuropharm.2018.11.009.  

Folding Underlies Bidirectional Role of GPR37/Pael-R in Parkinson Disease. Leinartaité L, Svenningsson P. Trends Pharmacol Sci. 2017 Aug;38(8):749-760. doi: 10.1016/j.tips.2017.05.006. Epub 2017 Jun 16. Review. 

Trace and monoamine receptors  

TAAR1´s role in the monoaminergic system of the brain 

TAAR1 is mainly expressed in the brain, pancreas and stomach. TAAR1 agonists include several drugs of abuse such as methamphetamine, amphetamine and MDMA but also some endogenous trace amines which occur via monoamine metabolism such as phenethylamine, tyramine and tryptamine. TAAR1 agonists cause marked decrease of dopamine neuron firing rate while TAAR1 antagonists produce an increase in activity. These effects have been replicated by using TAAR1 KO mice.

Our aim is to unveil the role of TAAR1 in neurodegenerative and neuropsychiatric disorders such as depression and Parkinson´s disease.

Selected publications: 

TAAR1 dependent and independent actions of tyramine in interaction with glutamate underlie central effects of monoamine oxidase inhibition. Mantas I, Vallianatou T, Yang Y, Shariatgorji M, Kalomoiri M, Fridjonsdottir E, Millan MJ, Zhang X, Andrén PE, Svenningsson P.   Biological Psychiatry, 2020, in press. DOI: https://doi.org/10.1016/j.biopsych.2020.12.008 

Modulation by Trace Amine-Associated Receptor 1 of Experimental Parkinsonism, L-DOPA Responsivity, and Glutamatergic Neurotransmission. Alvarsson A, Zhang X, Stan TL, Schintu N, Kadkhodaei B, Millan MJ, Perlmann T, Svenningsson P. J Neurosci. 2015 Oct 14;35(41):14057-69. 

Ketamine and novel rapid acting antidepressants

       Recent research has focused on finding novel, non-monoaminergic based, receptor targets for treatment-resistant depression. In particular, the glutamatergic system has become a focal point for drug development research. Glutamate is the major excitatory neurotransmitter and makes functional contributions to more than half of all synapses in the brain. It acts on eight types of metabotropic receptors (mGluR1-mGluR8) and three families of ionotropic receptors (including AMPA, kainate, and NMDA-receptor subunits). 

       Ketamine, or RS-2-2-Chlorophenyl-2-methylaminocyclohexanone, a derivate of phencyclidine, is a substance originally used as an anesthetic drug. Several clinical studies showed that a single subanesthetic dose of ketamine has antidepressant effects. Pharmacologically, ketamine can be classified as a non-selective, non-competitive, high-affinity NMDAR antagonist and by that it plays a big role in synaptic transmission of glutamate.

Our work aims to elucidate the molecular mechanisms in different brain areas linked to the action of ketamine and to investigate its role in synaptic plasticity. We hope that our work shall identify ketamine-like compounds with antidepressant actions, but fewer side effects.

Selected publications:

Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit. Yao N, Skiteva O, Zhang X, Svenningsson P, Chergui K. Mol Psychiatry. 2018 Oct;23(10):2066-2077. doi: 10.1038/mp.2017.239.

NMDA receptor antagonists ketamine and Ro25-6981 inhibit evoked release of glutamate in vivo in the subiculum. Stan TL, Alvarsson A, Branzell N, Sousa VC, Svenningsson P. Transl Psychiatry. 2014 Jun 3;4(6):e395. doi: 10.1038/tp.2014.39.