Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activity of certain G protein-coupled receptors (GPCRs) and of glutamate N-Methyl-D-aspartate receptors (NMDARs) is altered in both schizophrenia and depression. Using postmortem prefrontal cortex samples from subjects with schizophrenia or depression, we observed a series of opposite changes in the expression of signaling proteins that have been implicated in the cross-talk between GPCRs and NMDARs. Thus, the levels of HINT1 proteins and NMDAR NR1 subunits carrying the C1 cytosolic segment were increased in depressives and decreased in schizophrenics, respect to matched controls. The differences in NR1 C1 subunits were compensated for via altered expression of NR1 subunits lacking the C1 segment; thus, the total number of NR1 subunits was comparable among the three groups. GPCRs influence the function of NR1 C1-containing NMDARs via PKC/Src, and thus, the association of mu-opioid and dopamine 2 receptors with NR1 C1 subunits was augmented in depressives and decreased in schizophrenics. However, the association of cannabinoid 1 receptors (CB1Rs) with NR1 C1 remained nearly constant. Endocannabinoids, via CB1Rs, control the presence of NR1 C1 subunits in the neural membrane. Thus, an altered endocannabinoid system may contribute to the pathophysiology of schizophrenia and depression by modifying the HINT1-NR1 C1/GPCR ratio, thereby altering GPCR-NMDAR cross-regulation.
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PMID:Schizophrenia and depression, two poles of endocannabinoid system deregulation. 2924 10

Interaction of a single drug with multiple targets through "polypharmacology" is increasingly recognized as necessary for treatment of complex diseases, such as schizophrenia. G protein-coupled receptors (GPCRs) are major medicinal targets, and understanding the structural basis of both GPCR drug selectivity and promiscuity could provide novel avenues for drug development.
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PMID:To Bind or Not to Bind: Unravelling GPCR Polypharmacology. 2939 14

Oligodendrocytes are the myelin-producing cells of the central nervous system (CNS). A variety of brain disorders from "classical" demyelinating diseases, such as multiple sclerosis, stroke, schizophrenia, depression, Down syndrome and autism, are shown myelination defects. Oligodendrocyte myelination is regulated by a complex interplay of intrinsic, epigenetic and extrinsic factors. Gpr17 (G protein-coupled receptor 17) is a G protein-coupled receptor, and has been identified to be a regulator for oligodendrocyte development. Here, we demonstrate that the absence of Gpr17 enhances remyelination in vivo with a toxin-induced model whereby focal demyelinated lesions are generated in spinal cord white matter of adult mice by localized injection of LPC(L-a-lysophosphatidylcholine). The increased expression of the activated form of Erk1/2 (phospho-Erk1/2) in lesion areas suggested the potential role of Erk1/2 activity on the Gpr17-dependent modulation of myelination. The absence of Gpr17 enhances remyelination is correlate with the activated Erk1/2 (phospho-Erk1/2).Being a membrane receptor, Gpr17 represents an ideal druggable target to be exploited for innovative regenerative approaches to acute and chronic CNS diseases.
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PMID:G-Protein-Coupled Receptor Gpr17 Regulates Oligodendrocyte Differentiation in Response to Lysolecithin-Induced Demyelination. 2954 Jul 37

Label-free cellular assays using a biosensor provide new opportunities for studying G protein-coupled receptor (GPCR) signaling. As opposed to conventional in vitro assays, integrated receptor-mediated cellular responses are determined in real-time rather than a single downstream signaling pathway. In this study, we examined the potential of a label-free whole cell impedance-based biosensor system (i.e. xCELLigence) to study the pharmacology of one GPCR in particular, the mGlu2 receptor. This receptor is a target for the treatment of several psychiatric diseases such as schizophrenia and depression. After optimization of assay conditions to prevent interference of endogenous glutamate in the culture medium, detailed pharmacological assessments were performed. Concentration-response curves showed a concentration-dependent increase in impedance for agonists and positive allosteric modulators, whereas receptor inhibition by an antagonist or negative allosteric modulator resulted in a concentration-dependent decrease in cellular impedance. Interestingly, constitutive receptor activity was observed that was decreased by LY341495, which therefore behaved as an inverse agonist here, a property that was heretofore unappreciated. This was confirmed by concentration-dependent modulation of LY341495 potency and efficacy by a allosteric modulators. In summary, the use of the xCELLigence system to study mGlu2 receptor pharmacology was validated. This is the first class C GPCR to be characterized extensively by such method, opening new avenues to study receptor pharmacology including inverse agonism and demonstrating its value for future drug discovery efforts of mGlu receptors as well as other GPCRs.
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PMID:Constitutive activity of the metabotropic glutamate receptor 2 explored with a whole-cell label-free biosensor. 2960 27

The serotonin 5-HT2A and glutamate mGlu2 receptors continue to attract particular attention, given their implication in psychosis associated with schizophrenia and the mechanism of action of atypical antipsychotics and a new class of antipsychotics, respectively. A large body of evidence indicates a functional crosstalk between both receptors in the brain, but the underlying mechanisms are not entirely elucidated. Here, we have explored the influence of 5-HT2A receptor upon the phosphorylation pattern of mGlu2 receptor in light of the importance of specific phosphorylation events in regulating G protein-coupled receptor signaling and physiological outcomes. Among the five mGlu2 receptor-phosphorylated residues identified in HEK-293 cells, the phosphorylation of Ser843 was enhanced upon mGlu2 receptor stimulation by the orthosteric agonist LY379268 only in cells co-expressing the 5-HT2A receptor. Likewise, administration of LY379268 increased mGlu2 receptor phosphorylation at Ser843 in prefrontal cortex of wild-type mice but not 5-HT2A-/- mice. Exposure of HEK-293 cells co-expressing mGlu2 and 5-HT2A receptors to 5-HT also increased Ser843 phosphorylation state to a magnitude similar to that measured in LY379268-treated cells. In both HEK-293 cells and prefrontal cortex, Ser843 phosphorylation elicited by 5-HT2A receptor stimulation was prevented by the mGlu2 receptor antagonist LY341495, while the LY379268-induced effect was abolished by the 5-HT2A receptor antagonist M100907. Mutation of Ser843 into alanine strongly reduced Gi/o signaling elicited by mGlu2 or 5-HT2A receptor stimulation in cells co-expressing both receptors. Collectively, these findings identify mGlu2 receptor phosphorylation at Ser843 as a key molecular event that underlies the functional crosstalk between both receptors.
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PMID:5-HT2A receptor-dependent phosphorylation of mGlu2 receptor at Serine 843 promotes mGlu2 receptor-operated Gi/o signaling. 2985 99

The advent of the genomic era has led to the discovery of linkages of several genes and pathways to schizophrenia and autism spectrum disorder (ASD) that may serve as new biomarkers or therapeutic targets for these diseases. Two large-scale genetic studies published early in 2011 provided evidence that functional microduplications at 7q36.3, containing VIPR2, are a risk factor for schizophrenia. 7q36.3 microduplications were also reported to be significantly increased in ASD. VIPR2 encodes VPAC2, a seven transmembrane heterotrimeric G protein-coupled receptor that binds two homologous neuropeptides with high affinity, PACAP and VIP. These clinical studies demonstrate a VIPR2 genetic linkage to schizophrenia and ASD and should lead to novel insights into the etiology of these mental health disorders. However, the mechanism by which overactive VPAC2 signaling may lead to schizophrenia and ASD is unknown. In the present review, we will describe recent advances in the genetics of schizophrenia and attempt to discuss the pathophysiological role of altered VPAC2 signaling in psychiatric disorders.
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PMID:[Pathophysiological implication of the VPAC2 receptor in psychiatric disorders]. 2988 74

The dopamine (DA) D2 receptor (D2R) is an important target for the treatment of neuropsychiatric disorders such as schizophrenia and Parkinson's disease. However, the development of improved therapeutic strategies has been hampered by our incomplete understanding of this receptor's downstream signaling processes in vivo and how these relate to the desired and undesired effects of drugs. D2R is a G protein-coupled receptor (GPCR) that activates G protein-dependent as well as non-canonical arrestin-dependent signaling pathways. Whether these effector pathways act alone or in concert to facilitate specific D2R-dependent behaviors is unclear. Here, we report on the development of a D2R mutant that recruits arrestin but is devoid of G protein activity. When expressed virally in "indirect pathway" medium spiny neurons (iMSNs) in the ventral striatum of D2R knockout mice, this mutant restored basal locomotor activity and cocaine-induced locomotor activity in a manner indistinguishable from wild-type D2R, indicating that arrestin recruitment can drive locomotion in the absence of D2R-mediated G protein signaling. In contrast, incentive motivation was enhanced only by wild-type D2R, signifying a dissociation in the mechanisms that underlie distinct D2R-dependent behaviors, and opening the door to more targeted therapeutics.
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PMID:Arrestin recruitment to dopamine D2 receptor mediates locomotion but not incentive motivation. 3012 Apr 13

The histamine H3 receptor is a G protein-coupled receptor (GPCR) drug target that is highly expressed in the CNS, where it acts as both an auto- and hetero-receptor to regulate neurotransmission. As such, it has been considered as a relevant target in disorders as varied as Alzheimer's disease, schizophrenia, neuropathic pain and attention deficit hyperactivity disorder. A range of competitive antagonists/inverse agonists have progressed into clinical development, with pitolisant approved for the treatment of narcolepsy. Given the breadth of compounds developed and potential therapeutic indications, we assessed the comparative pharmacology of six investigational histamine H3 agents, including pitolisant, using native tissue and recombinant cells. Whilst all of the compounds tested displayed robust histamine H3 receptor inverse agonism and did not differentiate between the main H3 receptor splice variants, they displayed a wide range of affinities and kinetic properties, and included rapidly dissociating (pitolisant, S 38093-2, ABT-239) and slowly dissociating (GSK189254, JNJ-5207852, PF-3654746) agents. S 38093-2 had the lowest histamine H3 receptor affinity (pKB values 5.7-6.2), seemingly at odds with previously reported, potent in vivo activity in models of cognition. We show here that at pro-cognitive and anti-hyperalgesic/anti-allodynic doses, S 38093-2 preferentially occupies the mouse sigma-1 receptor in vivo, only engaging the histamine H3 receptor at doses associated with wakefulness promotion and neurotransmitter (histamine, ACh) release. Furthermore, pitolisant, ABT-239 and PF-3654746 also displayed appreciable sigma-1 receptor affinity, suggesting that this property differentiates clinically evaluated histamine H3 receptor antagonists and may play a role in their efficacy.
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PMID:Drug-receptor kinetics and sigma-1 receptor affinity differentiate clinically evaluated histamine H3 receptor antagonists. 3035 39

Most clinically available antipsychotic drugs (APDs) bind dopamine D2 receptors (D2R) at therapeutic concentrations, and it is thought that they suppress psychotic symptoms by serving as competitive antagonists of dopamine at D2R. Here, we present data that demonstrate that APDs act independently of dopamine at an intracellular pool of D2R to enhance transport of D2R to the cell surface and suggest that APDs can act as pharmacological chaperones at D2R. Among the first- and second-generation APDs that we tested, clozapine exhibited the lowest efficacy for translocating D2R to the cell surface. Thus, our observations could provide a cellular explanation for some of the distinct therapeutic characteristics of clozapine in schizophrenia. They also suggest that differential intracellular actions of APDs at their common G protein-coupled receptor (GPCR) target, D2R, could contribute to differences in their clinical profiles.
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PMID:The differential actions of clozapine and other antipsychotic drugs on the translocation of dopamine D2 receptors to the cell surface. 3067 May 97

The trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor widely expressed in the mammalian brain, particularly in limbic system and monoaminergic areas. It has proven to be an important modulator of dopaminergic, serotoninergic, and glutamatergic neurotransmission and is considered to be a potential useful target for the pharmacotherapy of neuropsychiatric disorders, including schizophrenia. One of the promising schizophrenia endophenotypes is a deficit in neurocognitive abilities manifested as mismatch negativity (MMN) deficit. This study examines the effect of TAAR1 partial agonist RO5263397 on the MMN-like response in freely moving C57BL/6 mice. Event-related potentials (ERPs) were recorded from awake mice in the oddball paradigm before and after RO5263397 administration. The RO5263397 (but not saline) administration increased the N40 amplitude in response to deviant stimuli. That provided the MMN-like difference at the 36-44 ms interval after the injection. The pitch deviance-elicited changes before the injection and in the control paradigm were established for the P68 component. After TAAR1 agonist administration the P68 amplitude in response both to standard and deviant stimuli was increased. These results suggest that the MMN-like response in mice may be modulated through TAAR1-dependent processes (possibly acting through the direct or indirect glutamate NMDA receptor modulation), indicating the TAAR1 agonists potential antipsychotic and pro-cognitive activity.
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PMID:Trace Amine-Associated Receptor 1 Agonist Modulates Mismatch Negativity-Like Responses in Mice. 3113 Aug 64


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