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Dopaminergic neurons express a heteromer composed of the dopamine D3 receptor and the α4ß2 nicotinic acetylcholine receptor, the D3R-nAChR heteromer, activated by both nicotine and dopamine D2 and D3 receptors agonists, such as quinpirole, and crucial for dopaminergic neuron homeostasis. We now report that D3R-nAChR heteromer activity is potentiated by 17-ß-estradiol which acts as a positive allosteric modulator by binding a specific domain on the α4 subunit of the nicotinic receptor protomer. In mouse dopaminergic neurons, in fact, 17-ß-estradiol significantly increased the ability of nicotine and quinpirole in promoting neuron dendritic remodeling and in protecting neurons against the accumulation of α-synuclein induced by deprivation of glucose, with a mechanism that does not involve the classical estrogen receptors. The potentiation induced by 17-ß-estradiol required the D3R-nAChR heteromer since either nicotinic receptor or dopamine D3 receptor antagonists and interfering TAT-peptides, but not the estrogen receptor antagonist fulvestrant, specifically prevented 17-ß-estradiol effects. Evidence of estrogens neuroprotection, mainly mediated by genomic mechanisms, have been provided, which is in line with epidemiological data reporting that females are less likely to develop Parkinson's Disease than males. Therefore, potentiation of D3R-nAChR heteromer activity may represent a further mechanism by which 17-ß-estradiol reduces dopaminergic neuron vulnerability.
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Our recent study revealed that fluorescent lamp light can penetrate deep into the brain of mice and rats leading to the development of typical histological characteristics associated with Parkinson's disease such as the loss of dopamine neurons in the substantia nigra. Monochromatic LED lights were thus used in this work to deepen our knowledge on the effects of the major wavelength peaks of fluorescent light on mouse and human dopaminergic cells. In particular, we exposed immortalized dopaminergic MN9D neuronal cells, primary cultures of mouse mesencephalic dopaminergic cells and human dopaminergic neurons differentiated from induced pluripotent stem cells (hiPSC) to different LED light wavelengths. We found that chronic exposure to LED light reduced overall undifferentiated MN9D cell number, with the most significant effects observed at wavelengths of 485 nm and 610 nm. Moreover, LED light especially at 610 nm was able to negatively impact on the survival of mouse mesencephalic dopaminergic cells and of human dopaminergic neurons derived from hiPSC. Notably, differentiated MN9D dopaminergic cells, which closely resemble mature dopamine neuronal phenotype, acutely exposed for 3 h at 610 nm, showed a clear increase in ROS production and cytotoxicity compared to controls undifferentiated MN9D cells. These increases were even more pronounced by the co-treatment with the oxidative agent H2O2. Collectively, these findings suggest that specific wavelengths, particularly those capable of penetrating deep into the brain, could potentially pose an environmental hazard in relation to Parkinson's disease.
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Neuronas Dopaminérgicas , Enfermedad de Parkinson , Humanos , Animales , Ratas , Enfermedad de Parkinson/patología , Peróxido de Hidrógeno/farmacología , Mesencéfalo , Sustancia NegraRESUMEN
We have established Noonan syndrome (NS)-derived induced pluripotent stem cell (iPSC) lines derived from peripheral blood mononuclear cells (PBMCs) of a family cohort carrying the heterozygous PTPN11 c.188 A > G (p.Y63C) mutation. The new iPSC lines were validated by confirming the normal karyotype and targeted mutation, the pluripotent gene expression, and the differentiation capacity into three germ layers.
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Células Madre Pluripotentes Inducidas , Síndrome de Noonan , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Síndrome de Noonan/genética , Síndrome de Noonan/metabolismo , Leucocitos Mononucleares , Mutación/genética , Heterocigoto , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genéticaRESUMEN
The heteromer composed of dopamine D1 and D3 receptors (D1R-D3R) has been defined as a structure able to trigger Erk1/2 and Akt signaling in a G protein-independent, beta-arrestin 1-dependent way that is physiologically expressed in the ventral striatum and is likely involved in the control of locomotor activity. Indeed, abnormal levels of D1R-D3R heteromer in the dorsal striatum have been correlated with the development of L-DOPA-induced dyskinesia (LID) in Parkinson's disease patients, a motor complication associated with striatal D1R signaling, thus requiring Gs protein and PKA activity to activate Erk1/2. Therefore, to clarify the role of the D1R/D3R heteromer in LID, we investigated the signaling pathway induced by the heteromer using transfected cells and primary mouse striatal neurons. Collectively, we found that in both the cell models, D1R/D3R heteromer-induced activation of Erk1/2 exclusively required the D1R molecular effectors, such as Gs protein and PKA, with the contribution of the phosphatase Shp-2 and beta-arrestins, indicating that heterodimerization with the D3R abolishes the specific D3R-mediated signaling but strongly allows D1R signals. Therefore, while in physiological conditions the D1R/D3R heteromer could represent a mechanism that strengthens the D1R activity, its pathological expression may contribute to the abnormal PKA-Shp-2-Erk1/2 pathway connected with LID.
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Dopamina , Levodopa , Animales , Ratones , beta-Arrestina 1 , beta-Arrestinas , Proteínas de Unión al GTP , Levodopa/farmacología , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Proteínas Tirosina Fosfatasas , Receptores de Dopamina D1 , Receptores de Dopamina D3RESUMEN
Neuronal nicotinic acetylcholine receptors (nAChRs) are widely distributed in both the peripheral and the central nervous systems. nAChRs exert a crucial modulatory influence on several brain biological processes; they are involved in a variety of neuronal diseases including Parkinson's disease, Alzheimer's disease, epilepsy, and nicotine addiction. The influence of nAChRs on brain function depends on the activity of other neurotransmitter receptors that co-exist with nAChRs on neurons. In fact, the crosstalk between receptors is an important mechanism of neurotransmission modulation and plasticity. This may be due to converging intracellular pathways but also occurs at the membrane level, because of direct physical interactions between receptors. In this line, this review is dedicated to summarizing how nAChRs and other ionotropic and metabotropic receptors interact and the relevance of nAChRs cross-talks in modulating various neuronal processes ranging from the classical modulation of neurotransmitter release to neuron plasticity and neuroprotection.
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Receptores Nicotínicos , Receptores Nicotínicos/metabolismo , Sistema Nervioso Central/metabolismo , Neuronas/metabolismo , Transmisión Sináptica/fisiología , Encéfalo/metabolismoRESUMEN
G protein-coupled receptors (GPCR) heterodimers represent new entities with unique pharmacological, signalling, and trafficking properties, with specific distribution restricted to those cells where the two interacting receptors are co-expressed. Like other GPCR, dopamine D3 receptors (D3R) directly interact with various receptors to form heterodimers: data showing the D3R physical interaction with both GPCR and non-GPCR receptors have been provided including D3R interaction with other dopamine receptors. The aim of this chapter is to summarize current knowledge of the distinct roles of heterodimers involving D3R, focusing on the D3R interaction with the dopamine D1 receptor (D1R): the D1R-D3R heteromer, in fact, has been postulated in both ventral and motor striatum. Interestingly, since both D1R and D3R have been implicated in several pathological conditions, including schizophrenia, motor dysfunctions, and substance use disorders, the D1R-D3R heteromer may represent a potential drug target for the treatment of these diseases.
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Dopamina , Receptores de Dopamina D3 , Receptores de Dopamina D3/metabolismo , Cuerpo EstriadoRESUMEN
Attention deficit and hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by alterations in the mesocorticolimbic and nigrostriatal dopaminergic pathways. Polymorphisms in the Synapsin III (Syn III) gene can associate with ADHD onset and even affect the therapeutic response to the gold standard ADHD medication, methylphenidate (MPH), a monoamine transporter inhibitor whose efficacy appears related with the stimulation of brain-derived neurotrophic factor (BDNF). Interestingly, we previously showed that MPH can bind Syn III, which can regulate neuronal development. These observations suggest that Syn III polymorphism may impinge on ADHD onset and response to therapy by affecting BDNF-dependent dopaminergic neuron development. Here, by studying zebrafish embryos exposed to Syn III gene knock-down (KD), Syn III knock-out (ko) mice and human induced pluripotent stem cells (iPSCs)-derived neurons subjected to Syn III RNA interference, we found that Syn III governs the earliest stages of dopaminergic neurons development and that this function is conserved in vertebrates. We also observed that in mammals Syn III exerts this function acting upstream of brain-derived neurotrophic factor (BDNF)- and cAMP-dependent protein kinase 5 (Cdk5)-stimulated dendrite development. Collectively, these findings own significant implications for deciphering the biological basis of ADHD.
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Neuronas Dopaminérgicas , Sinapsinas , Animales , Humanos , Ratones , Factor Neurotrófico Derivado del Encéfalo/genética , Dopamina , Neuronas Dopaminérgicas/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Metilfenidato/uso terapéutico , Ratones Noqueados , Sinapsinas/genética , Sinapsinas/metabolismo , Pez Cebra/metabolismoRESUMEN
Parkinson's disease (PD) is characterized by dopaminergic nigrostriatal neurons degeneration and Lewy body pathology, mainly composed of α-synuclein (αSyn) fibrillary aggregates. We recently described that the neuronal phosphoprotein Synapsin III (Syn III) participates in αSyn pathology in PD brains and is a permissive factor for αSyn aggregation. Moreover, we reported that the gene silencing of Syn III in a human αSyn transgenic (tg) mouse model of PD at a pathological stage, manifesting marked insoluble αSyn deposits and dopaminergic striatal synaptic dysfunction, could reduce αSyn aggregates, restore synaptic functions and motor activities and exert neuroprotective effects. Interestingly, we also described that the monoamine reuptake inhibitor methylphenidate (MPH) can recover the motor activity of human αSyn tg mice through a dopamine (DA) transporter-independent mechanism, which relies on the re-establishment of the functional interaction between Syn III and α-helical αSyn. These findings support that the pathological αSyn/Syn III interaction may constitute a therapeutic target for PD. Here, we studied MPH and some of its analogues as modulators of the pathological αSyn/Syn III interaction. We identified 4-methyl derivative I-threo as a lead candidate modulating αSyn/Syn III interaction and having the ability to reduce αSyn aggregation in vitro and to restore the motility of αSyn tg mice in vivo more efficiently than MPH. Our results support that MPH derivatives may represent a novel class of αSyn clearing agents for PD therapy.
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We have previously shown that the heteromer composed by the dopamine D3 receptor (D3R) and the nicotinic acetylcholine receptor (nAChR) (D3R-nAChR heteromer) is expressed in dopaminergic neurons, activated by nicotine and represents the molecular unit that, in these neurons, contributes to the modulation of critical events such as structural plasticity and neuroprotection. We now extended this study by investigating the D3R-nAChR heteromer properties using various cell models such as transfected HEK293 cells, primary cultures of mouse dopaminergic neurons and human dopaminergic neurons derived from induced pluripotent stem cells.We found that the D3R-nAChR heteromer is the molecular effector that transduces the remodeling properties not only associated with nicotine but also with D3R agonist stimulation: neither nAChR nor D3R, in fact, when express as monomers, are able to elicit these effects. Moreover, strong and sustained activation of the PI3K-ERK1/2/Akt pathways is coupled with D3R-nAChR heteromer stimulation, leading to the expression of the immediate-early gene c-Fos and to sustained phosphorylation of cytosolic p70 ribosomal S6 kinase (p70S6K), critical for dendritic remodeling. By contrast, while D3R stimulation results in rapid and transient activation of both Erk1/2 and Akt, that is PI3K-dependent, stimulation of nAChR is associated with persistent activation of Erk1/2 and Akt, in a PI3K-independent way. Thus, the D3R-nAChR heteromer and its ability to trigger the PI3K-ERK1/2/Akt signaling pathways may represent a novel target for preserving dopaminergic neurons healthy and for conferring neuronal protection against injuries.
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Receptores de Dopamina D3 , Receptores Nicotínicos , Animales , Neuronas Dopaminérgicas/metabolismo , Células HEK293 , Humanos , Sistema de Señalización de MAP Quinasas , Ratones , Nicotina/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Receptores de Dopamina D3/metabolismo , Receptores Nicotínicos/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Transducción de SeñalRESUMEN
Converging clinical and preclinical evidence demonstrates that depressive phenotypes are associated with synaptic dysfunction and dendritic simplification in cortico-limbic glutamatergic areas. On the other hand, the rapid antidepressant effect of acute ketamine is consistently reported to occur together with the rescue of dendritic atrophy and reduction of spine number induced by chronic stress in the hippocampus and prefrontal cortex of animal models of depression. Nevertheless, the molecular mechanisms underlying these morphological alterations remain largely unknown. Here, we found that miR-9-5p levels were selectively reduced in the hippocampus of rats vulnerable to Chronic Mild Stress (CMS), while acute subanesthetic ketamine restored its levels to basal condition in just 24h; miR-9-5p expression inversely correlated with the anhedonic phenotype. A decrease of miR-9-5p was reproduced in an in vitro model of stress, based on primary hippocampal neurons incubated with the stress hormone corticosterone. In both CMS animals and primary neurons, decreased miR-9-5p levels were associated with dendritic simplification, while treatment with ketamine completely rescued the changes. In vitro modulation of miR-9-5p expression showed a direct role of miR-9-5p in regulating dendritic length and spine density in mature primary hippocampal neurons. Among the putative target genes tested, Rest and Sirt1 were validated as biological targets in primary neuronal cultures. Moreover, in line with miR-9-5p changes, REST protein expression levels were remarkably increased in both CMS vulnerable animals and corticosterone-treated neurons, while ketamine completely abolished this alteration. Finally, the shortening of dendritic length in corticosterone-treated neurons was shown to be partly rescued by miR-9-5p overexpression and dependent on REST protein expression. Overall, our data unveiled the functional role of miR-9-5p in the remodeling of dendritic arbor induced by stress/corticosterone in vulnerable animals and its rescue by acute antidepressant treatment with ketamine.
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Progesterone (Pg) and estrogen (E) receptors (PgRs and ERs) are expressed in normal and neoplastic adrenal cortex, but their role is not fully understood. In literature, Pg demonstrated cytotoxic activity on AdrenoCortical Carcinoma (ACC) cells, while tamoxifen is cytotoxic in NCI-H295R cells. Here, we demonstrated that in ACC cell models, ERs were expressed in NCI-H295R cells with a prevalence of ER-ß over the ER-α.Metastasis-derived MUC-1 and ACC115m cells displayed a very weak ER-α/ß signal, while PgR cells were expressed, although at low level. Accordingly, these latter were resistant to the SERM tamoxifen and scarcely sensitive to Pg, as we observed a lower potency compared to NCI-H295R cells in cytotoxicity (IC50: MUC-1 cells: 67.58 µM (95%CI: 63.22-73.04), ACC115m cells: 51.76 µM (95%CI: 46.45-57.67) and cell proliferation rate. Exposure of NCI-H295R cells to tamoxifen induced cytotoxicity (IC50: 5.43 µM (95%CI: 5.18-5.69 µM) mainly involving ER-ß, as their nuclear localization increased after tamoxifen: Δ A.U. treated vs untreated: 12 h: +27.04% (p < 0.01); 24 h: +36.46% (p < 0.0001). This effect involved the SF-1 protein reduction: Pg: -36.34 ± 9.26%; tamoxifen: -46.25 ± 15.68% (p < 0.01). Finally, in a cohort of 36 ACC samples, immunohistochemistry showed undetectable/low level of ERs, while PgR demonstrated a higher expression. In conclusion, ACC experimental cell models expressed PgR and low levels of ER in line with data obtained in patient tissues, thus limiting the possibility of a clinical approach targeting ER. Interestingly, Pg exerted cytotoxicity also in metastatic ACC cells, although with low potency.
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Neoplasias de la Corteza Suprarrenal/patología , Carcinoma Corticosuprarrenal/patología , Progesterona/farmacología , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Tamoxifeno/farmacología , Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Neoplasias de la Corteza Suprarrenal/metabolismo , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Carcinoma Corticosuprarrenal/metabolismo , Antineoplásicos Hormonales/farmacología , Apoptosis , Proliferación Celular , Quimioterapia Combinada , Femenino , Humanos , Masculino , Progestinas/farmacología , Células Tumorales CultivadasRESUMEN
Peripheral blood mononuclear cells (PBMCs) derived from a healthy 40-year-old female were successfully transformed into induced pluripotent stem cells (iPSCs) by using the integration-free CytoTune-iPS Sendai Reprogramming method. The resulting iPSCs line exhibits a normal karyotype, expresses stemness markers and displays the differentiation capacity into the three germ layers. This human iPSCs line can be used as healthy control in disease modelling studies.
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Células Madre Pluripotentes Inducidas , Adulto , Diferenciación Celular , Reprogramación Celular , Femenino , Estratos Germinativos , Humanos , Leucocitos MononuclearesRESUMEN
Mutations in the leucine-rich repeat kinase 2 (LRRK2) are the most common genetic determinants of Parkinson's disease (PD), with the G2019S accounting for about 3% of PD cases. LRRK2 regulates various cellular processes, including vesicle trafficking that is crucial for receptor localization at the plasma membrane. In this study, induced pluripotent stem cells derived from 2 PD patients bearing the G2019S LRRK2 kinase activating mutation were used to generate neuronal cultures enriched in dopaminergic neurons. The results show that mutant LRRK2 prevents the membrane localization of both the dopamine D3 receptors (D3R) and the nicotinic acetylcholine receptors (nAChR) and the formation of the D3R-nAChR heteromer, a molecular unit crucial for promoting neuronal homeostasis and preserving dopaminergic neuron health. Interestingly, D3R and nAChR as well as the corresponding heteromer membrane localization were rescued by inhibiting the abnormally increased kinase activity. Thus, the altered membrane localization of the D3R-nAChR heteromer associated with mutation in LRRK2 might represent a pre-degenerative feature of dopaminergic neurons contributing to the special vulnerability of this neuronal population.
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Membrana Celular/metabolismo , Neuronas Dopaminérgicas/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Mutación , Enfermedad de Parkinson/genética , Receptores de Dopamina D3/metabolismo , Receptores Nicotínicos/metabolismo , HumanosRESUMEN
The progressive neuropathological damage seen in Parkinson's disease (PD) is thought to be related to the spreading of aggregated forms of α-synuclein. Clearance of extracellular α-synuclein released by degenerating neurons may be therefore a key mechanism to control the concentration of α-synuclein in the extracellular space. Several molecular chaperones control misfolded protein accumulation in the extracellular compartment. Among these, clusterin, a glycoprotein associated with Alzheimer's disease, binds α-synuclein aggregated species and is present in Lewy bodies, intraneuronal aggregates mainly composed by fibrillary α-synuclein. In this study, using murine primary astrocytes with clusterin genetic deletion, human-induced pluripotent stem cell (iPSC)-derived astrocytes with clusterin silencing and two animal models relevant for PD we explore how clusterin affects the clearance of α-synuclein aggregates by astrocytes. Our findings showed that astrocytes take up α-synuclein preformed fibrils (pffs) through dynamin-dependent endocytosis and that clusterin levels are modulated in the culture media of cells upon α-synuclein pffs exposure. Specifically, we found that clusterin interacts with α-synuclein pffs in the extracellular compartment and the clusterin/α-synuclein complex can be internalized by astrocytes. Mechanistically, using clusterin knock-out primary astrocytes and clusterin knock-down hiPSC-derived astrocytes we observed that clusterin limits the uptake of α-synuclein pffs by cells. Interestingly, we detected increased levels of clusterin in the adeno-associated virus- and the α-synuclein pffs- injected mouse model, suggesting a crucial role of this chaperone in the pathogenesis of PD. Overall, our observations indicate that clusterin can limit the uptake of extracellular α-synuclein aggregates by astrocytes and, hence, contribute to the spreading of Parkinson pathology.
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Enfermedad de Parkinson , alfa-Sinucleína , Animales , Astrocitos , Clusterina/genética , Humanos , Cuerpos de Lewy , Ratones , alfa-Sinucleína/genéticaRESUMEN
Converging clinical and preclinical evidence has shown that dysfunction of the glutamate system is a core feature of major depressive disorder. In this context, the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has raised growing interest as fast acting antidepressant. Using the chronic mild stress (CMS) rat model of depression, performed in male rats, we aimed at analyzing whether hippocampal specific changes in subunit expression and regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or NMDA ionotropic receptors and in metabotropic glutamate receptors could be associated with behavioral vulnerability/resilience to CMS. We also assessed whether acute ketamine (10 mg/kg) was able to dampen the alterations in CMS vulnerable animals. Although chronic stress and ketamine had no effect on ionotropic glutamate receptors mRNAs (expression, RNA editing and splicing), we found selective modulations in their protein expression, phosphorylation and localization at synaptic membranes. AMPA GluA2 expression at synaptic membranes was significantly increased only in CMS resilient rats (although a trend was found also in vulnerable animals), while its phosphorylation at Ser880 was higher in both CMS resilient and vulnerable rats, a change partially dampened by ketamine. In the hippocampus from all stressed groups, despite NMDA receptor expression levels were reduced in total extract, the levels of GluN2B-containing NMDA receptors were remarkably increased in synaptic membranes. Finally, mGlu2 underwent a selective downregulation in stress vulnerable animals, which was completely restored by acute ketamine. Overall, these results are in line with a hypofunction of activity-dependent glutamatergic synaptic transmission induced by chronic stress exposure in all the animals, as suggested by the alterations of ionotropic glutamate receptors expression and localization at synaptic level. At the same time, the selective modulation of mGlu2 receptor, confirms its previously hypothesized functional role in regulating stress vulnerability and, for the first time here, suggests a mGlu2 involvement in the fast antidepressant effect of ketamine.
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Hipocampo/metabolismo , Ketamina/farmacología , Receptores AMPA/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Estrés Psicológico/metabolismo , Animales , Enfermedad Crónica , Antagonistas de Aminoácidos Excitadores/farmacología , Hipocampo/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , Receptores AMPA/antagonistas & inhibidores , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Estrés Psicológico/psicologíaRESUMEN
Novel and complementary experimental models are required for investigating the molecular mechanisms underlying the resistance to the available therapies of patients with major depression (Treatment-Resistant Depression, TRD) that occurs in at least one third of patients and need to be deeply investigated. Here, we have established a patient-specific disease model for TRD by reprogramming peripheral blood mononuclear cells (PBMCs) from two TRD patients into induced pluripotent stem cells (iPSCs), using non-integrating Sendai virus. These lines show the typical morphology of pluripotent cells, express pluripotency markers and displayed in vitro differentiation potential toward cells of the three embryonic germ layers.
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Células Madre Pluripotentes Inducidas , Diferenciación Celular , Reprogramación Celular , Depresión , Humanos , Leucocitos Mononucleares , Virus Sendai/genéticaRESUMEN
The dopamine (DA) D3 receptor (D3R) plays a pivotal role in the control of several functions, including motor activity, rewarding and motivating behavior and several aspects of cognitive functions. Recently, it has been reported that the D3R is also involved in the regulation of neuronal development, in promoting structural plasticity and in triggering key intracellular events with neuroprotective potential. A new role for D3R-dependent neurotransmission has thus been proposed both in preserving DA neuron homeostasis in physiological conditions and in preventing pathological alterations that may lead to neurodegeneration. Interestingly, there is evidence that nicotinic acetylcholine receptors (nAChR) located on DA neurons also provide neurotrophic support to DA neurons, an effect requiring functional D3R and suggesting the existence of a positive cross-talk between these receptor systems. Increasing evidence suggests that, as with the majority of G protein-coupled receptors (GPCR), the D3R directly interacts with other receptors to form new receptor heteromers with unique functional and pharmacological properties. Among them, we recently identified a receptor heteromer containing the nAChR and the D3R as the molecular effector of nicotine-mediated neurotrophic effects. This review summarizes the functional and pharmacological characteristics of D3R, including the capability to form active heteromers as pharmacological targets for specific neurodegenerative disorders. In particular, the molecular and functional features of the D3R-nAChR heteromer will be especially discussed since it may represent a possible key etiologic effector for DA-related pathologies, such as Parkinson's disease (PD), and a target for drug design.
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Receptores de Dopamina D3/química , Receptores de Dopamina D3/metabolismo , Receptores Nicotínicos/metabolismo , Animales , Humanos , Plasticidad Neuronal , Neuroprotección , Multimerización de ProteínaRESUMEN
The loss of dopaminergic neurons of the nigrostriatal system underlies the onset of the typical motor symptoms of Parkinson's disease (PD). Lewy bodies (LB) and Lewy neurites (LN), proteinaceous inclusions mainly composed of insoluble α-synuclein (α-syn) fibrils are key neuropathological hallmarks of the brain of affected patients. Compelling evidence supports that in the early prodromal phases of PD, synaptic terminal and axonal alterations initiate and drive a retrograde degeneration process culminating with the loss of nigral dopaminergic neurons. This notwithstanding, the molecular triggers remain to be fully elucidated. Although it has been shown that α-syn fibrillary aggregation can induce early synaptic and axonal impairment and cause nigrostriatal degeneration, we still ignore how and why α-syn fibrillation begins. Nuclear factor-κB (NF-κB) transcription factors, key regulators of inflammation and apoptosis, are involved in the brain programming of systemic aging as well as in the pathogenesis of several neurodegenerative diseases. The NF-κB family of factors consists of five different subunits (c-Rel, p65/RelA, p50, RelB, and p52), which combine to form transcriptionally active dimers. Different findings point out a role of RelA in PD. Interestingly, the nuclear content of RelA is abnormally increased in nigral dopamine (DA) neurons and glial cells of PD patients. Inhibition of RelA exert neuroprotection against (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) MPTP and 1-methyl-4-phenylpyridinium (MPP+) toxicity, suggesting that this factor decreases neuronal resilience. Conversely, the c-Rel subunit can exert neuroprotective actions. We recently described that mice deficient for c-Rel develop a PD-like motor and non-motor phenotype characterized by progressive brain α-syn accumulation and early synaptic changes preceding the frank loss of nigrostriatal neurons. This evidence supports that dysregulations in this transcription factors may be involved in the onset of PD. This review highlights observations supporting a possible interplay between NF-κB dysregulation and α-syn pathology in PD, with the aim to disclose novel potential mechanisms involved in the pathogenesis of this disorder.