Publications by authors named "Kjell Fuxe"

336 Publications

The Balance of MU-Opioid, Dopamine D2 and Adenosine A2A Heteroreceptor Complexes in the Ventral Striatal-Pallidal GABA Antireward Neurons May Have a Significant Role in Morphine and Cocaine Use Disorders.

Front Pharmacol 2021 15;12:627032. Epub 2021 Mar 15.

Department of Neuroscience, Karolinska Institutet, Biomedicum, Stockholm, Sweden.

The widespread distribution of heteroreceptor complexes with allosteric receptor-receptor interactions in the CNS represents a novel integrative molecular mechanism in the plasma membrane of neurons and glial cells. It was proposed that they form the molecular basis for learning and short-and long-term memories. This is also true for drug memories formed during the development of substance use disorders like morphine and cocaine use disorders. In cocaine use disorder it was found that irreversible A2AR-D2R complexes with an allosteric brake on D2R recognition and signaling are formed in increased densities in the ventral enkephalin positive striatal-pallidal GABA antireward neurons. In this perspective article we discuss and propose how an increase in opioid heteroreceptor complexes, containing MOR-DOR, MOR-MOR and MOR-D2R, and their balance with each other and A2AR-D2R complexes in the striatal-pallidal enkephalin positive GABA antireward neurons, may represent markers for development of morphine use disorders. We suggest that increased formation of MOR-DOR complexes takes place in the striatal-pallidal enkephalin positive GABA antireward neurons after chronic morphine treatment in part through recruitment of MOR from the MOR-D2R complexes due to the possibility that MOR upon morphine treatment can develop a higher affinity for DOR. As a result, increased numbers of D2R monomers/homomers in these neurons become free to interact with the A2A receptors found in high densities within such neurons. Increased numbers of A2AR-D2R heteroreceptor complexes are formed and contribute to enhanced firing of these antireward neurons due to loss of inhibitory D2R protomer signaling which finally leads to the development of morphine use disorder. Development of cocaine use disorder may instead be reduced through enkephalin induced activation of the MOR-DOR complex inhibiting the activity of the enkephalin positive GABA antireward neurons. Altogether, we propose that these altered complexes could be pharmacological targets to modulate the reward and the development of substance use disorders.
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http://dx.doi.org/10.3389/fphar.2021.627032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005530PMC
March 2021

Amplification of potential thermogenetic mechanisms in cetacean brains compared to artiodactyl brains.

Sci Rep 2021 Mar 9;11(1):5486. Epub 2021 Mar 9.

Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.

To elucidate factors underlying the evolution of large brains in cetaceans, we examined 16 brains from 14 cetartiodactyl species, with immunohistochemical techniques, for evidence of non-shivering thermogenesis. We show that, in comparison to the 11 artiodactyl brains studied (from 11 species), the 5 cetacean brains (from 3 species), exhibit an expanded expression of uncoupling protein 1 (UCP1, UCPs being mitochondrial inner membrane proteins that dissipate the proton gradient to generate heat) in cortical neurons, immunolocalization of UCP4 within a substantial proportion of glia throughout the brain, and an increased density of noradrenergic axonal boutons (noradrenaline functioning to control concentrations of and activate UCPs). Thus, cetacean brains studied possess multiple characteristics indicative of intensified thermogenetic functionality that can be related to their current and historical obligatory aquatic niche. These findings necessitate reassessment of our concepts regarding the reasons for large brain evolution and associated functional capacities in cetaceans.
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http://dx.doi.org/10.1038/s41598-021-84762-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970898PMC
March 2021

The Role of Central Serotonin Neurons and 5-HT Heteroreceptor Complexes in the Pathophysiology of Depression: A Historical Perspective and Future Prospects.

Int J Mol Sci 2021 Feb 15;22(4). Epub 2021 Feb 15.

Department of Neuroscience, Karolinska Institutet, Biomedicum, Lab B0851, Solnavägen 9, 17 177 Stockholm, Sweden.

Serotonin communication operates mainly in the extracellular space and cerebrospinal fluid (CSF), using volume transmission with serotonin moving from source to target cells (neurons and astroglia) via energy gradients, leading to the diffusion and convection (flow) of serotonin. One emerging concept in depression is that disturbances in the integrative allosteric receptor-receptor interactions in highly vulnerable 5-HT1A heteroreceptor complexes can contribute to causing major depression and become novel targets for the treatment of major depression (MD) and anxiety. For instance, a disruption and/or dysfunction in the 5-HT1A-FGFR1 heteroreceptor complexes in the raphe-hippocampal serotonin neuron systems can contribute to the development of MD. It leads inter alia to reduced neuroplasticity and potential atrophy in the raphe-cortical and raphe-striatal 5-HT pathways and in all its forebrain networks. Reduced 5-HT1A auto-receptor function, increased plasticity and trophic activity in the midbrain raphe 5-HT neurons can develop via agonist activation of allosteric receptor-receptor interactions in the 5-HT1A-FGFR1 heterocomplex. Additionally, the inhibitory allosteric receptor-receptor interactions in the 5-HT1AR-5-HT2AR isoreceptor complex therefore likely have a significant role in modulating mood, involving a reduction of postjunctional 5-HT1AR protomer signaling in the forebrain upon activation of the 5-HT2AR protomer. In addition, oxytocin receptors (OXTRs) play a significant and impressive role in modulating social and cognitive related behaviors like bonding and attachment, reward and motivation. Pathological blunting of the OXTR protomers in 5-HT2AR and especially in 5-HT2CR heteroreceptor complexes can contribute to the development of depression and other types of psychiatric diseases involving disturbances in social behaviors. The 5-HTR heterocomplexes are novel targets for the treatment of MD.
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http://dx.doi.org/10.3390/ijms22041927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919680PMC
February 2021

Molecular, biochemical and behavioural evidence for a novel oxytocin receptor and serotonin 2C receptor heterocomplex.

Neuropharmacology 2021 02 12;183:108394. Epub 2020 Nov 12.

APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland. Electronic address:

The complexity of oxytocin-mediated functions is strongly associated with its modulatory effects on other neurotransmission systems, including the serotonin (5-hydroxytryptamine, 5-HT) system. Signalling between oxytocin (OT) and 5-HT has been demonstrated during neurodevelopment and in the regulation of specific emotion-based behaviours. It is suggested that crosstalk between neurotransmitters is driven by interaction between their specific receptors, particularly the oxytocin receptor (OTR) and the 5-hydroxytryptamine 2C receptor (5-HTR), but evidence for this and the downstream signalling consequences that follow are lacking. Considering the overlapping central expression profiles and shared involvement of OTR and 5-HTR in certain endocrine functions and behaviours, including eating behaviour, social interaction and locomotor activity, we investigated the existence of functionally active OTR/5-HTR heterocomplexes. Here, we demonstrate evidence for a potential physical interaction between OTR and 5-HTRin vitro in a cellular expression system using flow cytometry-based FRET (fcFRET). We could recapitulate this finding under endogenous expression levels of both receptors via in silico analysis of single cell transcriptomic data and ex vivo proximity ligation assay (PLA). Next, we show that co-expression of the OTR/5-HTR pair resulted in a significant depletion of OTR-mediated Gαq-signalling and significant changes in receptor trafficking. Of note, attenuation of OTR-mediated downstream signalling was restored following pharmacological blockade of the 5-HTR. Finally, we demonstrated a functional relevance of this novel heterocomplex, in vivo, as 5-HTR antagonism increased OT-mediated hypoactivity in mice. Overall, we provide compelling evidence for the formation of functionally active OTR/5-HTR heterocomplexes, adding another level of complexity to OTR and 5-HTR signalling functionality. This article is part of the special issue on Neuropeptides.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108394DOI Listing
February 2021

Galanin and neuropeptide Y interactions elicit antidepressant activity linked to neuronal precursor cells of the dentate gyrus in the ventral hippocampus.

J Cell Physiol 2021 May 12;236(5):3565-3578. Epub 2020 Oct 12.

Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.

A need for new antidepressants is necessary since traditional antidepressants have several flaws. Neuropeptide Y(NPY) Y1 receptor (NPYY1R) and galanin (GAL) receptor 2 (GALR2) interact in several regions of the limbic system, including the hippocampus. The current study assesses the antidepressant effects induced by GALR2 and NPYY1R coactivation, together with the evaluation of cell proliferation through 5-Bromo-2'-deoxyuridine expression within the dentate gyrus of the ventral hippocampus (vDG). We employed in situ proximity ligation assay to manifest GALR2/NPYY1R heteroreceptor complexes. Additionally, the expression pattern of GALR2 and the activation of the extracellular-regulated kinases (ERK) pathway after GALR2 and NPYY1R costimulation in cell cultures were examined. GALR2 and NPYY1R coactivation resulted in sustained antidepressant behaviors in the FST after 24 h, linked to increased cell proliferation in the vDG. Moreover, an increased density of GALR2/NPYY1R heteroreceptor complexes was observed in vDG, on doublecortin-expressing neuroblasts. Recruitment of the GALR2 expression to the plasma membrane was observed upon the coactivation of GALR2 and NPYY1R in cell cultures, presumably associated to the enhanced effects on the activation of ERK pathway. GALR2 may promote the GALR2/NPYY1R heteroreceptor complexes formation in the ventral hippocampus. It may induce a transformation of cell proliferation toward a neuronal lineage by enhancement of ERK pathway. Thus, it may give the mechanism for the antidepressant behavior observed. These results may provide the basis for the development of heterobivalent agonist pharmacophores, targeting GALR2/NPYY1R heteromers, especially in the neuronal precursor cells of the dentate gyrus in the ventral hippocampus for the novel treatment of depression.
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http://dx.doi.org/10.1002/jcp.30092DOI Listing
May 2021

Evidence for the existence of A2AR-TrkB heteroreceptor complexes in the dorsal hippocampus of the rat brain: Potential implications of A2AR and TrkB interplay upon ageing.

Mech Ageing Dev 2020 09 18;190:111289. Epub 2020 Jun 18.

Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy.

Adenosine A2A receptors (A2AR) are crucial in facilitating the BDNF action on synaptic transmission in the rat hippocampus primarily upon ageing. Furthermore, it has been suggested that A2AR-Tropomyosin related kinase B receptor (TrkB) crosstalk has a pivotal role in adenosine A2AR-mediated modulation of the BDNF action on hippocampal plasticity. Considering the impact of the above receptors interplay on what concerns BDNF-induced enhancement of synaptic transmission, gaining a better insight into the mechanisms behind this powerful crosstalk becomes of primary interest. Using in situ proximity ligation assay (PLA), the existence of a direct physical interaction between adenosine A2AR and TrkB is demonstrated. The A2AR-TrkB heteroreceptor complexes show a heterogeneous distribution within the rat dorsal hippocampus. High densities of the heteroreceptor complexes were observed in the pyramidal cell layers of CA1-CA3 regions and in the polymorphic layer of the dentate gyrus (DG). The stratum radiatum of the CA1-3 regions showed positive PLA signal in contrast to the oriens region. The molecular and granular layers of the DG also lacked significant densities of PLA positive heteroreceptor complexes, but subgranular zone showed some PLA positive cells. Their allosteric receptor-receptor interactions may significantly modulate BDNF signaling impacting on hippocampal plasticity which is impaired upon ageing.
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http://dx.doi.org/10.1016/j.mad.2020.111289DOI Listing
September 2020

Adenosine AReceptors in Substance Use Disorders: A Focus on Cocaine.

Cells 2020 06 1;9(6). Epub 2020 Jun 1.

Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, 31-343 Kraków, Poland.

Several psychoactive drugs can evoke substance use disorders (SUD) in humans and animals, and these include psychostimulants, opioids, cannabinoids (CB), nicotine, and alcohol. The etiology, mechanistic processes, and the therapeutic options to deal with SUD are not well understood. The common feature of all abused drugs is that they increase dopamine (DA) neurotransmission within the mesocorticolimbic circuitry of the brain followed by the activation of DA receptors. D receptors were proposed as important molecular targets for SUD. The findings showed that D receptors formed heteromeric complexes with other GPCRs, which forced the addiction research area in new directions. In this review, we updated the view on the brain D receptor complexes with adenosine (A)2A receptors (AR) and discussed the role of AR in different aspects of addiction phenotypes in laboratory animal procedures that permit the highly complex syndrome of human drug addiction. We presented the current knowledge on the neurochemical in vivo and ex vivo mechanisms related to cocaine use disorder (CUD) and discussed future research directions for AR heteromeric complexes in SUD.
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http://dx.doi.org/10.3390/cells9061372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348840PMC
June 2020

Multiple Adenosine-Dopamine (A2A-D2 Like) Heteroreceptor Complexes in the Brain and Their Role in Schizophrenia.

Cells 2020 04 27;9(5). Epub 2020 Apr 27.

Department of Neuroscience, Karolinska Institutet, 17170 Stockholm, Sweden.

In the 1980s and 1990s, the concept was introduced that molecular integration in the Central Nervous System could develop through allosteric receptor-receptor interactions in heteroreceptor complexes presents in neurons. A number of adenosine-dopamine heteroreceptor complexes were identified that lead to the A-D heteromer hypothesis of schizophrenia. The hypothesis is based on strong antagonistic A-D receptor-receptor interactions and their presence in the ventral striato-pallidal GABA anti-reward neurons leading to reduction of positive symptoms. Other types of adenosine A heteroreceptor complexes are also discussed in relation to this disease, such as A-D and A-D heteroreceptor complexes as well as higher order A-D-mGluR5 and A-D-Sigma1R heteroreceptor complexes. The A receptor protomer can likely modulate the function of the D receptors of relevance for understanding cognitive dysfunction in schizophrenia. A-D-mGluR5 complex is of interest since upon A/mGluR5 coactivation they appear to synergize in producing strong inhibition of the D2 receptor protomer. For understanding the future of the schizophrenia treatment, the vulnerability of the current A-Dlike receptor complexes will be tested in animal models of schizophrenia. A-D-Simag1R complexes hold the highest promise through Sigma1R enhancement of inhibition of D2R function. In line with this work, Lara proposed a highly relevant role of adenosine for neurobiology of schizophrenia.
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http://dx.doi.org/10.3390/cells9051077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290895PMC
April 2020

Existence of FGFR1-5-HT1AR heteroreceptor complexes in hippocampal astrocytes. Putative link to 5-HT and FGF2 modulation of hippocampal gamma oscillations.

Neuropharmacology 2020 06 27;170:108070. Epub 2020 Mar 27.

Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; Observatorio Cubano de Neurociencias, Zayas 50, 62100, Yaguajay, Cuba; Department of Biomolecular Science, Section of Physiology, University of Urbino, Campus Scientifico Enrico Mattei, via Ca' le Suore 2, I-61029, Urbino, Italy. Electronic address:

The majority of the fibroblast growth factor receptor 1-serotonin 1 A receptor (FGFR1-5-HT1AR) heterocomplexes in the hippocampus appeared to be located mainly in the neuronal networks and a relevant target for antidepressant drugs. Through a neurochemical and electrophysiological analysis it was therefore tested in the current study if astrocytic FGFR1-5-HT1AR heterocomplexes also exist in hippocampus. They may modulate the structure and function of astroglia in the hippocampus leading to possible changes in the gamma oscillations. Localization of hippocampal FGFR1-5-HT1AR heterocomplexes in astrocytes was found using in situ proximity ligation assay combined with immunohistochemistry using glial fibrillary acidic protein (GFAP) immunoreactivity as a marker for astroglia. Acute i.c.v. treatment with 8-OH-DPAT alone or together with basic fibroblast growth factor (FGF2) significantly increased FGFR1-5-HT1AR heterocomplexes in the GFAP positive cells, especially in the polymorphic layer of the dentate gyrus (PoDG) but also in the CA3 area upon combined treatment. No other hippocampal regions were studied. Also, structural plasticity changes were observed in the astrocytes, especially in the PoDG region, upon these pharmacological treatments. They may also be of relevance for enhancing the astroglial volume transmission with increased modulation of the neuronal networks in the regions studied. The effects of combined FGF2 and 5-HT agonist treatments on gamma oscillations point to a significant antagonistic interaction in astroglial FGFR1-5-HT1AR heterocomplexes that may contribute to counteraction of the 5-HT1AR-mediated decrease of gamma oscillations. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108070DOI Listing
June 2020

Acute cocaine treatment enhances the antagonistic allosteric adenosine A2A-dopamine D2 receptor-receptor interactions in rat dorsal striatum without increasing significantly extracellular dopamine levels.

Pharmacol Rep 2020 Apr 2;72(2):332-339. Epub 2020 Mar 2.

Department of Neuroscience, Karolinska Institutet, Biomedicum 8B Solnavägen 9, 171 65, Solna, Sweden.

Background: Antagonistic adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) receptor-receptor interactions have previously been demonstrated in A2AR-D2R heteroreceptor complexes in the rat dorsal striatum. They mainly involve a reduction of affinity in the high-affinity component of the D2R agonist binding site upon activation in vivo of the A2AR by an A2AR agonist. Upon cocaine self-administration, this antagonistic A2AR-D2R interaction disappeared in the dorsal striatum.

Methods: In the current experiments, it was tested whether such modifications in the antagonistic A2AR-D2R receptor-receptor interactions can develop also after an acute systemic injection of a low cocaine dose (1 mg/kg; sc).

Results: Microdialysis experiments indicated that acute cocaine did not significantly alter the extracellular dopamine levels in the dorsal striatum of the awake Wistar rats. Competition dopamine receptor binding experiments demonstrated that in the acute cocaine group, the A2AR agonist CGS-21680 produced significantly larger increases in the D2R K values (reduction of high-affinity) versus the saline-injected (i.e. control) group. Furthermore, in the dorsal striatum membrane preparation from acute cocaine-injected rats, CGS-21680 also produced significant increases in the D2R K values (reduction of low-affinity) and in the proportion of D2Rs in the high-affinity state (RH). Such significant effects were not observed with CGS-21680 in the control group.

Conclusions: The molecular mechanism involved in the acute cocaine-induced increase in the antagonistic allosteric A2AR-D2R receptor-receptor interactions may be an increased formation of higher-order complexes A2AR-D2R-sigma1R in which cocaine by binding to the sigma1R protomer also allosterically enhances the inhibitory A2AR-D2R interaction in this receptor complex.
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http://dx.doi.org/10.1007/s43440-020-00069-3DOI Listing
April 2020

A2AR Transmembrane 2 Peptide Administration Disrupts the A2AR-A2AR Homoreceptor but Not the A2AR-D2R Heteroreceptor Complex: Lack of Actions on Rodent Cocaine Self-Administration.

Int J Mol Sci 2019 Dec 3;20(23). Epub 2019 Dec 3.

Department of Neuroscience, Karolinska Institutet, 16175 Stockholm, Sweden.

It was previously demonstrated that rat adenosine A2AR transmembrane V peptide administration into the nucleus accumbens enhances cocaine self-administration through disruption of the A2AR-dopamine (D2R) heteroreceptor complex of this region. Unlike human A2AR transmembrane 4 (TM4) and 5 (TM5), A2AR TM2 did not interfere with the formation of the A2AR-D2R heteroreceptor complex in cellular models using BRET assay. A2AR TM2 was proposed to be part of the of the receptor interface of the A2AR homomer instead and was therefore tested in the current article for effects on rat cocaine self-administration using rat A2AR synthetic TM2 peptide bilaterally injected into the nucleus accumbens. The injected A2AR TM2 peptide failed to significantly counteract the inhibitory action of the A2AR agonist CGS 21680 (0.1 mg/Kg) on cocaine self-administration. In line with these results, the microinjected A2AR TM2 peptide did not reduce the number of proximity ligation assay blobs identifying A2AR-D2R heteroreceptor complexes in the nucleus accumbens. In contrast, the A2AR TM2 peptide significantly reduced the number of A2AR-A2AR homoreceptor complexes in the nucleus accumbens. As to effects on the receptor-receptor interactions in the A2AR-D2R heteroreceptor complexes, the A2AR TM2 peptide did not alter the significant increase in the D2R Ki, high values produced by the A2AR agonist CGS 21680 ex vivo in the ventral striatum. The results indicate that the accumbal A2AR-A2AR homomeric complexes are not involved in mediating the A2AR agonist-induced inhibition of cocaine self-administration.
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http://dx.doi.org/10.3390/ijms20236100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928905PMC
December 2019

OSU-6162, a Sigma1R Ligand in Low Doses, Can Further Increase the Effects of Cocaine Self-Administration on Accumbal D2R Heteroreceptor Complexes.

Neurotox Res 2020 Feb 28;37(2):433-444. Epub 2019 Nov 28.

Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Cocaine was previously shown to act at the Sigma1R which is a target for counteracting cocaine actions. It therefore becomes of interest to test if the monoamine stabilizer (-) OSU-6162 (OSU-6162) with a nanomolar affinity for the Sigma1R can acutely modulate in low doses the effects of cocaine self-administration. In behavioral studies, OSU-6162 (5 mg/kg, s.c.) did not significantly change the number of active lever pressing and cocaine infusions. However, a trend to reduce cocaine readouts was found after 3 days of treatment. In contrast, in maintenance of cocaine self-administration, the proximity ligation assay performed on brains from rats pretreated with OSU-6162 showed highly significant increases in the density of the D2R-Sigma1R heteroreceptor complexes in the shell of the nucleus accumbens versus OSU-6162 induced increases in this region of yoked saline rats. In cocaine self-administration, highly significant increases were also induced by OSU-6162 in the A2AR-D2R heteroreceptor complexes in the nucleus accumbens shell versus vehicle-treated rats. Furthermore, ex vivo, the A2AR agonist CGS21680 (100 nM) produced a marked and significant increase of the D2R Ki high values in the OSU-6162-treated versus vehicle-treated rats under maintenance of cocaine self-administration. These results indicate a substantial increase in the inhibitory allosteric A2AR-D2R interactions following cocaine self-administration upon activation by the A2AR agonist ex vivo. The current results indicate that OSU-6162 via its high affinity for the Sigma1R may increase the number of accumbal shell D2R-Sigma1R and A2AR-D2R heteroreceptor complexes associated with further increases in the antagonistic A2AR-D2R interactions in cocaine self-administration.
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http://dx.doi.org/10.1007/s12640-019-00134-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989596PMC
February 2020

Differential allosteric modulation within dopamine DR - neurotensin NTS1R and DR - serotonin 5-HTR receptor complexes gives bias to intracellular calcium signalling.

Sci Rep 2019 11 8;9(1):16312. Epub 2019 Nov 8.

Department of Chemistry and Pharmacy, Molecular and Clinical Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.

Proceeding investigations of G protein-coupled receptor (GPCR) heterocomplexes have demonstrated that the dopamine D2 receptor (DR), one of the hub receptors in the physiology of schizophrenia, interacts with both the neurotensin NTS1 (NTS1R) and the serotonin 5-HT receptor (5-HTR) in cell lines and rodent brain tissue. In situ proximity ligation assay and BRET-based saturation experiments confirmed interacting receptor assemblies in HEK293T and neuronal HT22 cells. The NTS1R agonist NT(8-13) reduces the Gα-mediated calcium signal in the NTS1R-DR complex compared to the NTS1R monomer which could be reversed by DR antagonists. The bivalent ligand CS148 (NTS1R-agonistic, DR-antagonistic) increased the calcium response addressing the dimer, consistent with the effect of the monovalent ligands suggesting an allosteric DR-mediated modulation. In contrast, the 5-HTR-DR heteromer did not show a calcium-altering receptor-receptor interaction. Despite their common coupling-preference for Gα, 5-HTR and NTS1R supposedly interact with DR each in a unique mode. This remarkably diverse ligand-mediated signalling in two different DR heteroreceptor complexes illustrates the complexity of receptor-receptor interactions and their potential of modifying cell responses to external stimuli. Therefore, GPCR heteromers may provide a very promising novel target for the therapy of neuropsychiatric disorders.
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http://dx.doi.org/10.1038/s41598-019-52540-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6841725PMC
November 2019

Desipramine restores the alterations in circadian entrainment induced by prenatal exposure to glucocorticoids.

Transl Psychiatry 2019 10 17;9(1):263. Epub 2019 Oct 17.

Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Alterations in circadian rhythms are closely linked to depression, and we have shown earlier that progressive alterations in circadian entrainment precede the onset of depression in mice exposed in utero to excess glucocorticoids. The aim of this study was to investigate whether treatment with the noradrenaline reuptake inhibitor desipramine (DMI) could restore the alterations in circadian entrainment and prevent the onset of depression-like behavior. C57Bl/6 mice were exposed to dexamethasone (DEX-synthetic glucocorticoid analog, 0.05 mg/kg/day) between gestational day 14 and delivery. Male offspring aged 6 months (mo) were treated with DMI (10 mg/kg/day in drinking water) for at least 21 days before behavioral testing. We recorded spontaneous activity using the TraffiCage™ system and found that DEX mice re-entrained faster than controls after an abrupt advance in light-dark cycle by 6 h, while DMI treatment significantly delayed re-entrainment. Next we assessed the synchronization of peripheral oscillators with the central clock (located in the suprachiasmatic nucleus-SCN), as well as the mechanisms required for entrainment. We found that photic entrainment of the SCN was apparently preserved in DEX mice, but the expression of clock genes in the hippocampus was not synchronized with the light-dark cycle. This was associated with downregulated mRNA expression for arginine vasopressin (AVP; the main molecular output entraining peripheral clocks) in the SCN, and for glucocorticoid receptor (GR; required for the negative feedback loop regulating glucocorticoid secretion) in the hippocampus. DMI treatment restored the mRNA expression of AVP in the SCN and enhanced GR-mediated signaling by upregulating GR expression and nuclear translocation in the hippocampus. Furthermore, DMI treatment at 6 mo prevented the onset of depression-like behavior and the associated alterations in neurogenesis in 12-mo-old DEX mice. Taken together, our data indicate that DMI treatment enhances GR-mediated signaling and restores the synchronization of peripheral clocks with the SCN and support the hypothesis that altered circadian entrainment is a modifiable risk factor for depression.
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http://dx.doi.org/10.1038/s41398-019-0594-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797805PMC
October 2019

Oligomeric Receptor Complexes and Their Allosteric Receptor-Receptor Interactions in the Plasma Membrane Represent a New Biological Principle for Integration of Signals in the CNS.

Front Mol Neurosci 2019 25;12:230. Epub 2019 Sep 25.

Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.

G protein-coupled receptors (GPCRs) not only exist as monomers but also as homomers and heteromers in which allosteric receptor-receptor interactions take place, modulating the functions of the participating GPCR protomers. GPCRs can also form heteroreceptor complexes with ionotropic receptors and receptor tyrosine kinases modulating their function. Furthermore, adaptor proteins interact with receptor protomers and modulate their interactions. The state of the art is that the allosteric receptor-receptor interactions are reciprocal, highly dynamic and substantially alter the signaling, trafficking, recognition and pharmacology of the participating protomers. The pattern of changes appears to be unique for each heteromer and can favor antagonistic or facilitatory interactions or switch the G protein coupling from e.g., Gi/o to Gq or to beta-arrestin signaling. It lends a new dimension to molecular integration in the nervous system. Future direction should be aimed at determining the receptor interface involving building models of selected heterodimers. This will make design of interface-interfering peptides that specifically disrupt the heterodimer possible. This will help to determine the functional role of the allosteric receptor-receptor interactions as well as the integration of signals at the plasma membrane by the heteroreceptor complexes, vs. integration of the intracellular signaling pathways. Integration of signals also at the plasma membrane seems crucial in view of the hypothesis that learning and memory at a molecular level takes place by reorganization of homo and heteroreceptor complexes in the postsynaptic membrane. Homo and heteroreceptor complexes are in balance with each other, and their disbalance is linked to disease. Targeting heteroreceptor complexes represents a novel strategy for the treatment of brain disorders.
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http://dx.doi.org/10.3389/fnmol.2019.00230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773811PMC
September 2019

Can Allosteric Receptor-Protein Interactions in Receptor Complexes Be a Molecular Mechanism Involved in Cancer Immune Therapy?

Front Endocrinol (Lausanne) 2019 20;10:574. Epub 2019 Aug 20.

Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Based on the work in the Central Nervous System with discoveries of allosteric receptor-receptor interactions in homo- and heteroreceptor complexes representing a major integrative mechanism in synapses and extrasynaptic regions, it is proposed that a similar mechanism may exist in the immunological synapses. We discuss a putative additional molecular mechanism for the ability of the inhibitory T cell signaling proteins CTLA-4 and PD-1 and the adenosine A2AR to diminish T cell activation leading to enhancement of cancer development. We suggest that in the same immunological synapse involving T cells and antigen presenting cells multiple heteroreceptor complexes may participate and be in balance with each other. Their composition can vary between functional states and among different types of T cells. The T cell receptor (TCR) and its accelerators, strongly enhancing T cell activation, can be under inhibitory control by T cell signaling proteins CTLA4 and PD-1 and also the adenosine A2AR through inhibitory allosteric receptor-receptor interactions in different types of heteroreceptor complexes. As a result, inhibitory tumor induced immunosuppression can develop due to a dominance of the inhibitory signaling causing a brake on the TCR and/or its accelerator and the cancer immunotherapy becomes blocked.
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http://dx.doi.org/10.3389/fendo.2019.00574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710404PMC
August 2019

Increased Ethanol Consumption and Locomotion Develop upon Ethanol Deprivation in Rats Overexpressing the Adenosine (A) Receptor.

Neuroscience 2019 10 23;418:133-148. Epub 2019 Aug 23.

Department of Neuroscience, Karolinska Institute, Retzius väg 8, 171 77 Stockholm, Sweden.

Preclinical data indicate that ethanol produces behavioral effects that can be regulated by many neurotransmitters and neuromodulators like adenosine (A). The most important receptors with respect to the rewarding effects of ethanol seem to be the A receptors. This study used a transgenic strategy, specifically rats overexpressing the A receptor, to characterize the neurobiological mechanisms of ethanol consumption as measured by intermittent access to 20% ethanol in a two-bottle choice paradigm. In this model, no change in ethanol consumption was observed in transgenic animals compared to wild type controls during the acquisition/maintenance phase. Following alcohol deprivation, only transgenic rats overexpressing the A receptor exhibited escalation of ethanol consumption and drank more (by ca. 90%), but not significantly, ethanol than did the wild type rats. During ethanol withdrawal, the immobility time of rats overexpressing the A receptor in the forced swim test was lower than that of wild type rats. Moreover, transgenic rats withdrawn from ethanol, compared to the drug-naive transgenic animals, exhibited an increase above 70% in locomotion. The results indicated that the overexpression of A receptors may be a risk factor for the escalation of ethanol consumption despite the reduction in depression-like signs of ethanol withdrawal.
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http://dx.doi.org/10.1016/j.neuroscience.2019.08.030DOI Listing
October 2019

Potentiation of cannabinoid signaling in microglia by adenosine A receptor antagonists.

Glia 2019 12 19;67(12):2410-2423. Epub 2019 Aug 19.

Centro de Investigación en Red, Enfermedades Neurodegenerativas (CiberNed), Instituto de Salud Carlos III, Madrid, Spain.

Neuroprotective M2-skewed microglia appear as promising to alter the course of neurodegenerative diseases and G protein-coupled receptors (GPCRs) are potential targets to achieve such microglial polarization. A common feature of adenosine A (A R) and cannabinoid CB (CB R) GPCRs in microglia is that their expression is upregulated in Alzheimer's disease (AD). On the one hand, CB R seems a target for neuroprotection, delaying neurodegenerative processes like those associated to AD or Parkinson's diseases. A R antagonists reduce amyloid burden and improve cognitive performance and memory in AD animal models. We here show a close interrelationship between these two receptors in microglia; they are able to physically interact and affect the signaling of each other, likely due to conformational changes within the A -CB receptor heteromer (A -CB Het). Particularly relevant is the upregulation of A -CB Het expression in samples from the APP , AD transgenic mice model. The most relevant finding, confirmed in both heterologous cells and in primary cultures of microglia, was that blockade of A receptors results in increased CB R-mediated signaling. This heteromer-specific feature suggests that A R antagonists would potentiate, via microglia, the neuroprotective action of endocannabinoids with implications for AD therapy.
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http://dx.doi.org/10.1002/glia.23694DOI Listing
December 2019

Heterodimerization of Mu Opioid Receptor Protomer with Dopamine D Receptor Modulates Agonist-Induced Internalization of Mu Opioid Receptor.

Biomolecules 2019 08 14;9(8). Epub 2019 Aug 14.

Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, 9000 Ghent, Belgium.

The interplay between the dopamine (DA) and opioid systems in the brain is known to modulate the additive effects of substances of abuse. On one hand, opioids serve mankind by their analgesic properties, which are mediated via the mu opioid receptor (MOR), a Class A G protein-coupled receptor (GPCR), but on the other hand, they pose a potential threat by causing undesired side effects such as tolerance and dependence, for which the exact molecular mechanism is still unknown. Using human embryonic kidney 293T (HEK 293T) and HeLa cells transfected with MOR and the dopamine D receptor (DR), we demonstrate that these receptors heterodimerize, using an array of biochemical and biophysical techniques such as coimmunoprecipitation (co-IP), bioluminescence resonance energy transfer (BRET), Fӧrster resonance energy transfer (FRET), and functional complementation of a split luciferase. Furthermore, live cell imaging revealed that DR, when coexpressed with MOR, slowed down internalization of MOR, following activation with the MOR agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO).
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http://dx.doi.org/10.3390/biom9080368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722706PMC
August 2019

Conventional and Novel Pharmacological Approaches to Treat Dopamine-Related Disorders: Focus on Parkinson's Disease and Schizophrenia.

Neuroscience 2020 07 23;439:301-318. Epub 2019 Jul 23.

Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.

The dopaminergic system integrated by cell groups distributed in several brain regions exerts a modulatory role in brain. Particularly important for this task are the mesencephalic dopamine neurons, which from the substantia nigra and ventral tegmental area project to the dorsal striatum and the cortical/subcortical limbic systems, respectively. Dopamine released from these neurons operates mainly via the short distance extrasynaptic volume transmission and activates five different dopaminergic receptor subtypes modulating synaptic GABA and glutamate transmission. To accomplish this task dopaminergic neurons keep mutual modulating interactions with neurons of other neurotransmitter systems, including allosteric receptor-receptor interactions in heteroreceptor complexes. As a result of its modulatory role dopaminergic mechanisms are involved in either the etiology or physiopathology of many brain diseases such as Parkinsońs disease and schizophrenia. The aim of this work is to review some novel and conventional approaches that either have been used or are currently employed to treat these diseases. Particular attention is paid to the approaches derived from the knowledge recently acquired in the realm of receptor-receptor interactions taking place through multiple dopamine heteroreceptor complexes in the plasma membrane. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.
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http://dx.doi.org/10.1016/j.neuroscience.2019.07.026DOI Listing
July 2020

On the G Protein-Coupled Receptor Neuromodulation of the Claustrum.

Neurochem Res 2020 Jan 6;45(1):5-15. Epub 2019 Jun 6.

Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 17177, Stockholm, Sweden.

G protein-coupled receptors modulate the synaptic glutamate and GABA transmission of the claustrum. The work focused on the transmitter-receptor relationships in the claustral catecholamine system and receptor-receptor interactions between kappa opioid receptors (KOR) and SomatostatinR2 (SSTR2) in claustrum. Methods used involved immunohistochemistry and in situ proximity ligation assay (PLA) using confocal microscopy. Double immunolabeling studies on dopamine (DA) D1 receptor (D1R) and tyrosine hydroxylase (TH) immunoreactivities (IR) demonstrated that D1R IR existed in almost all claustral and dorsal endopiriform nucleus (DEn) nerve cell bodies, known as glutamate projection neurons, and D4R IR in large numbers of nerve cell bodies of the claustrum and DEn. However, only a low to moderate density of TH IR nerve terminals was observed in the DEn versus de few scattered TH IR terminals found in the claustrum. These results indicated that DA D1R and D4R transmission in the rat operated via long distance DA volume transmission in the rat claustrum and DEn to modulate claustral-sensory cortical glutamate transmission. Large numbers of these glutamate projection neurons also expressed KOR and SSTR2 which formed KOR-SSTR2 heteroreceptor complexes using PLA. Such receptor-receptor interactions can finetune the activity of the glutamate claustral-sensory cortex projections from inhibition to enhancement of their sensory cortex signaling. This can give the sensory cortical regions significant help in deciding on the salience to be given to various incoming sensory stimuli.
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http://dx.doi.org/10.1007/s11064-019-02822-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942600PMC
January 2020

Galanin (1-15)-fluoxetine interaction in the novel object recognition test. Involvement of 5-HT1A receptors in the prefrontal cortex of the rats.

Neuropharmacology 2019 09 22;155:104-112. Epub 2019 May 22.

Universidad de Málaga, Instituto de Investigación Biomédica de Málaga, Facultad de Medicina, Campus de Teatinos s/n, 29071, Málaga, Spain. Electronic address:

Galanin (1-15) [GAL(1-15)] participates in mood regulation and depression. GAL(1-15) is also able to enhance the antidepressant effects induced by Fluoxetine (FLX) in the forced swimming test through interaction between GALR1-GALR2 and 5-HT1A receptors that induced changes in the binding characteristics and mRNA of the 5-HT1AR in the hippocampus. Since the medial prefrontal cortex (mPFC) is a core region for the interaction between emotional processing and cognition with a high density of 5-HT1AR and GALR1 and GALR2, we have analyzed the binding characteristics and mRNA levels of 5-HT1AR in the mPFC after GAL(1-15)-FLX administration in the rats. GAL(1-15) increased the Kd and the Bmax of the 5HT1AR agonist binding in the mPFC as well as the mRNA levels of 5-HT1AR in mPFC. Moreover, GAL(1-15) reversed the effects of memory impairment induced by FLX(10 mg/kg) in the Novel Object Recognition task. GALR2 was involved in these effects, since the specific GALR2 antagonist M871 blocked GAL(1-15) mediated actions at behavioral level. On the contrary GAL(1-15) did not reverse the effect of FLX in the Object Location Memory task. In conclusion, our results describe an interactions between GAL(1-15) and FLX in the mPFC involving interactions at the 5-HT1AR receptor level in the plasma membrane with changes at the transcriptional level with implications also at functional level. The GALR1-GALR2-5-HT1A heteroreceptor could be postulated to be used to reverse some of the adverse effects of FLX on memory processes.
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http://dx.doi.org/10.1016/j.neuropharm.2019.05.023DOI Listing
September 2019

Role of the galanin N-terminal fragment (1-15) in anhedonia: Involvement of the dopaminergic mesolimbic system.

J Psychopharmacol 2019 06 13;33(6):737-747. Epub 2019 May 13.

1 Universidad de Málaga, Facultad de Medicina, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Campus de Teatinos s/n, 29071, Málaga, Spain.

Background: Anhedonia is a core feature of depressive disorders. The galanin N-terminal fragment (1-15) plays a role in mood regulation since it induces depression and anxiogenic-like effects in rats. In this study, we analysed galanin N-terminal fragment (1-15) actions in anhedonic-like behaviours in rats using operant and non-operant tests and the areas involved with these effects.

Methods: Galanin N-terminal fragment (1-15) effects were analysed in saccharin self-administration, sucrose preference, novelty-suppressed feeding and female urine sniffing tests. The areas involved in galanin N-terminal fragment (1-15)-mediated effects were studied with positron emission tomography for imaging, and we analysed the ventral tegmental area and nucleus accumbens. Galanin N-terminal fragment (1-15) had effects on the mRNA expression of the dopamine transporters Dat and Vmat2; the C-Fos gene; the dopamine receptors D1, D2, D3, D5; and the galanin receptors 1 and 2.

Results: Galanin N-terminal fragment (1-15) at a concentration of 3 nmol induced a strong anhedonia-like phenotype in all tests. The involvement of galanin receptor 2 was demonstrated with the galanin receptor 2 antagonist M871 (3 nmol). The 18F-fluorodeoxyglucose positron emission tomography images indicated the action of galanin N-terminal fragment (1-15) over several nuclei of the limbic system. Galanin N-terminal fragment (1-15)-mediated effects also involved changes in the expression of Dat, Vmat2, D3 and galanin receptors in the ventral tegmental area as well as the expression of C-Fos, D1, D2 and D3 and TH immunoreactivity in the nucleus accumbens.

Conclusions: Our results indicated that galanin N-terminal fragment (1-15) exerts strong anhedonic-like effects and that this effect was accompanied by changes in the dopaminergic mesolimbic system. These results may provide a basis for the development of novel therapeutic strategies using galanin N-terminal fragment (1-15) analogues for the treatment of depression and reward-related diseases.
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http://dx.doi.org/10.1177/0269881119844188DOI Listing
June 2019

Understanding receptor heteromerization and its allosteric integration of signals.

Neuropharmacology 2019 07 2;152:1-3. Epub 2019 May 2.

Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Biomolecular Science, Section of Physiology, University of Urbino, Campus Scientifico Enrico Mattei, via Ca' le Suore 2, I-61029, Urbino, Italy; Observatorio Cubano de Neurociencias, Grupo Bohío-Estudio, Zayas 50, 62100, Yaguajay, Cuba. Electronic address:

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http://dx.doi.org/10.1016/j.neuropharm.2019.05.001DOI Listing
July 2019

Attenuation of Oxytocin and Serotonin 2A Receptor Signaling through Novel Heteroreceptor Formation.

ACS Chem Neurosci 2019 07 8;10(7):3225-3240. Epub 2019 May 8.

APC Microbiome Ireland , University College Cork , Cork , Ireland.

The oxytocin receptor (OTR) and the 5-hydroxytryptamine 2A receptor (5-HTR) are expressed in similar brain regions modulating central pathways critical for social and cognition-related behaviors. Signaling crosstalk between their endogenous ligands, oxytocin (OT) and serotonin (5-hydroxytryptamine, 5-HT), highlights the complex interplay between these two neurotransmitter systems and may be indicative of the formation of heteroreceptor complexes with subsequent downstream signaling changes. In this study, we assess the possible formation of OTR-5HTR heteromers in living cells and the functional downstream consequences of this receptor-receptor interaction. First, we demonstrated the existence of a physical interaction between the OTR and 5-HTR, using a flow cytometry-based FRET approach and confocal microscopy. Furthermore, we investigated the formation of this specific heteroreceptor complex in the brain sections using the Proximity Ligation Assay (PLA). The OTR-5HTR heteroreceptor complexes were identified in limbic regions (including hippocampus, cingulate cortex, and nucleus accumbens), key regions associated with cognition and social-related behaviors. Next, functional cellular-based assays to assess the OTR-5HTR downstream signaling crosstalk showed a reduction in potency and efficacy of OT and OTR synthetic agonists, carbetocin and WAY267464, on OTR-mediated Gαq signaling. Similarly, the activation of 5-HTR by the endogenous agonist, 5-HT, also revealed attenuation in Gαq-mediated signaling. Finally, altered receptor trafficking within the cell was demonstrated, indicative of cotrafficking of the OTR/5-HTR pair. Overall, these results constitute a novel mechanism of specific interaction between the OT and 5-HT neurotransmitters via OTR-5HTR heteroreceptor formation and provide potential new therapeutic strategies in the treatment of social and cognition-related diseases.
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http://dx.doi.org/10.1021/acschemneuro.8b00665DOI Listing
July 2019

Acute Cocaine Enhances Dopamine DR Recognition and Signaling and Counteracts DR Internalization in Sigma1R-DR Heteroreceptor Complexes.

Mol Neurobiol 2019 Oct 10;56(10):7045-7055. Epub 2019 Apr 10.

Department of Neuroscience, Karolinska Institutet, Biomedicum (B0851). Solnavägen 9, 171 77, Stockholm, Sweden.

The current study was performed to establish the actions of nanomolar concentrations of cocaine, not blocking the dopamine transporter, on dopamine D2 receptor (DR)-sigma 1 receptor (δ1R) heteroreceptor complexes and the DR protomer recognition, signaling and internalization in cellular models. We report the existence of DR-δ1R heteroreceptor complexes in subcortical limbic areas as well as the dorsal striatum, with different distribution patterns using the in situ proximity ligation assay. Also, through BRET, these heteromers were demonstrated in HEK293 cells. Furthermore, saturation binding assay demonstrated that in membrane preparations of HEK293 cells coexpressing DR and δ1R, cocaine (1 nM) significantly increased the DR B values over cells singly expressing DR. CREB reporter luc-gene assay indicated that coexpressed δ1R significantly reduced the potency of the DR-like agonist quinpirole to inhibit via DR activation the forskolin induced increase of the CREB signal. In contrast, the addition of 100 nM cocaine was found to markedly increase the quinpirole potency to inhibit the forskolin-induced increase of the CREB signal in the DR-δ1R cells. These events were associated with a marked reduction of cocaine-induced internalization of DR protomers in DR-δ1R heteromer-containing cells vs DR singly expressing cells as studied by means of confocal analysis of DR-δ1R trafficking and internalization. Overall, the formation of DR-δ1R heteromers enhanced the ability of cocaine to increase the DR protomer function associated with a marked reduction of its internalization. The existence of DR-δ1R heteromers opens up a new understanding of the acute actions of cocaine.
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http://dx.doi.org/10.1007/s12035-019-1580-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728299PMC
October 2019

On Nobel Laureate Arvid Carlsson.

Authors:
Kjell Fuxe

J Neural Transm (Vienna) 2019 Apr;126(4):357

Department of Neuroscience, Karolinska Institutet, Biomedicum, Stockholm, Sweden.

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http://dx.doi.org/10.1007/s00702-019-01994-1DOI Listing
April 2019

Adenosine heteroreceptor complexes in the basal ganglia are implicated in Parkinson's disease and its treatment.

J Neural Transm (Vienna) 2019 04 14;126(4):455-471. Epub 2019 Jan 14.

Department of Neuroscience, Karolinska Institutet, Biomedicum, B0851, Solnavägen 9, 17177, Stockholm, Sweden.

The adenosine homo, iso and heteroreceptor complexes in the basal ganglia play a highly significant role in modulating the indirect and direct pathways and the striosomal projections to the nigro-striatal DA system. The major adenosine receptor complexes in the striato-pallidal GABA neurons can be the A2AR-D2R and A2AR-D2R-mGluR5 receptor complexes, in which A2AR protomers and mGluR5 protomers can allosterically interact to inhibit D2R protomer signaling. Through a reorganization of these heteroreceptor complexes upon chronic dopaminergic treatment a pathological and prolonged inhibition of D2R receptor protomer signaling can develop with motor inhibition and wearing off of the therapeutic effects of levodopa and dopamine receptor agonists. The direct pathway is enriched in D1R in and around glutamate synapses enhancing the ability of these GABA neurons to be activated and increase motor initiation. The brake on these GABA neurons is in this case exerted by A1R forming A1R-D1R heteroreceptor complexes in which they allosterically inhibit D1R signaling and thereby reduce motor initiation. Upon chronic levodopa treatment a reorganization of the D1R heteroreceptor complexes develops with the formation of putative A1R-D1R-D3 in addition to D1R-D3R complexes in which D3R enhances D1R protomer signaling and may make the A1R protomer brake less effective. Alpha-synuclein monomers-dimers are postulated to form complexes with A2AR homo and heteroprotomers in the plasma membrane enhancing alpha-synuclein aggregation and toxicity. The alpha-synuclein fibrils formed in the A2AR enriched dendritic spines of the striato-pallidal GABA neurons may reach the surrounding DA terminals via extracellular-vesicle-mediated volume transmission involving internalization of the vesicles and their cargo (alpha-synuclein fibrils) into the vulnerable DA terminals, enhancing their degeneration followed by retrograde flow of these fibrils in the DA axons to the vulnerable nigral DA nerve cells.
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http://dx.doi.org/10.1007/s00702-019-01969-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456481PMC
April 2019

A2AR-D2R Heteroreceptor Complexes in Cocaine Reward and Addiction.

Trends Pharmacol Sci 2018 12 29;39(12):1008-1020. Epub 2018 Oct 29.

Department of Neuroscience, Karolinska Institutet, Solnavägen 9, Stockholm, Sweden. Electronic address:

The concept of allosteric receptor-receptor interactions in G protein-coupled receptor homo- and heteroreceptor complexes in which they physically interact provides a new dimension to molecular integration in the brain. The receptor-receptor interactions dynamically change recognition, pharmacology, signaling, and trafficking of the participating receptors. Among the receptor complexes, disruption of the A2A receptor-dopamine D2 receptor (A2AR-D2R) complex by an A2AR agonist has been shown to fully block the inhibition of cocaine self-administration. Cocaine induced pathological A2AR-D2R-Sigma1R complexes may form a long-term memory with a strong and permanent D2R brake, leading to cocaine addiction. These heteroreceptor complexes can potentially be targeted for future pharmacotherapy of cocaine addiction by using heterobivalent compounds or A2AR-D2R receptor interface-interfering peptides that disrupt the A2AR-D2R-Sigma1R complexes.
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http://dx.doi.org/10.1016/j.tips.2018.10.007DOI Listing
December 2018

Mapping the Interface of a GPCR Dimer: A Structural Model of the A Adenosine and D Dopamine Receptor Heteromer.

Front Pharmacol 2018 30;9:829. Epub 2018 Aug 30.

Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.

The A adenosine (AR) and D dopamine (DR) receptors form oligomers in the cell membrane and allosteric interactions across the AR-DR heteromer represent a target for development of drugs against central nervous system disorders. However, understanding of the molecular determinants of AR-DR heteromerization and the allosteric antagonistic interactions between the receptor protomers is still limited. In this work, a structural model of the AR-DR heterodimer was generated using a combined experimental and computational approach. Regions involved in the heteromer interface were modeled based on the effects of peptides derived from the transmembrane (TM) helices on AR-DR receptor-receptor interactions in bioluminescence resonance energy transfer (BRET) and proximity ligation assays. Peptides corresponding to TM-IV and TM-V of the AR blocked heterodimer interactions and disrupted the allosteric effect of AR activation on DR agonist binding. Protein-protein docking was used to construct a model of the AR-DR heterodimer with a TM-IV/V interface, which was refined using molecular dynamics simulations. Mutations in the predicted interface reduced AR-DR interactions in BRET experiments and altered the allosteric modulation. The heterodimer model provided insights into the structural basis of allosteric modulation and the technique developed to characterize the AR-DR interface can be extended to study the many other G protein-coupled receptors that engage in heteroreceptor complexes.
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http://dx.doi.org/10.3389/fphar.2018.00829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125358PMC
August 2018