Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Numerous research has pointed out that serotonin2c (5-HT2C) receptor, a subtype of 5-HT receptors belonging to the G-protein-coupled receptor superfamily, modulates the activity of mesencephalic dopamine (DA) neurons, the dysfunction of which is involved in devastating diseases such as schizophrenia, Parkinson's disease, and drug addiction. In the present study, using in vivo intracerebral microdialysis and Chinese hamster ovary (CHO) cells expressing 5-HT2C receptors to identify appropriate 5-HT2C receptor ligands, we sought to determine whether the property of 5-HT2C receptors to spontaneously activate intracellular signaling pathways in vitro (constitutive activity) participates in the tonic inhibitory control that they exert on DA release in the rat striatum and nucleus accumbens in vivo. In CHO cells, the purported antagonist 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f] indole hydrochloride (SB 206553), but not 6-chloro-5-methyl-1-[6-(2-methylpiridin-3-yloxy)pyridin-3-yl carbamoyl] indoline (SB 242084), decreased basal inositol phosphate accumulation, thus behaving as a 5-HT2C inverse agonist. Its effect was prevented by SB 242084. In vivo, SB 206553 (1-10 mg/kg) elicited a dose-dependent and clear-cut increase in accumbal and striatal DA release compared with SB 242084 (1-10 mg/kg), and the 5-HT2C agonist S-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine hydrochloride (Ro-60-0175) (0.3-3 mg/kg) inhibited DA release. Pretreatment by SB 242084 reversed the change in DA release elicited by Ro-60-0175 and SB 206553. Furthermore, SB 206553-stimulated DA release was insensitive to reduction of 5-HT neuronal function induced by the 5-HT1A agonist (+/-)-8-hydroxy-2-dipropylaminotetralin or intra-raphe injections of 5,7-dihydroxytryptamine neurotoxin. The obtained results provide the first in vivo evidence that constitutive activity of the 5-HT2C receptor tonically inhibits mesencephalic DA neurons and underscore the need for a better understanding of the pathophysiological role of constitutive receptor activity.
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PMID:Constitutive activity of the serotonin2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens. 1505 2

In the pursuit of improved treatments for Parkinson's disease (PD), the adenosine A(2A) receptor has emerged as an attractive nondopaminergic target. Based on the compelling behavioral pharmacology and selective basal ganglia expression of this G-protein-coupled receptor, its antagonists are now crossing the threshold of clinical development as adjunctive symptomatic treatment for relatively advanced PD. The antiparkinsonian potential of A(2A) antagonism has been boosted further by recent preclinical evidence that A(2A) antagonists might favorably alter the course as well as the symptoms of the disease. Convergent epidemiological and laboratory data have suggested that A(2A) blockade may confer neuroprotection against the underlying dopaminergic neuron degeneration. In addition, rodent and nonhuman primate studies have raised the possibility that A(2A) receptor activation contributes to the pathophysiology of dyskinesias-problematic motor complications of standard PD therapy--and that A(2A) antagonism might help prevent them. Realistically, despite being targeted to basal ganglia pathophysiology, A(2A) antagonists may be expected to have other beneficial and adverse effects elsewhere in the central nervous system (e.g., on mood and sleep) and in the periphery (e.g., on immune and inflammatory processes). The thoughtful design of new clinical trials of A(2A) antagonists should take into consideration these counterbalancing hopes and concerns and may do well to shift toward a broader set of disease-modifying as well as symptomatic indications in early PD.
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PMID:Therapeutic potential of adenosine A(2A) receptor antagonists in Parkinson's disease. 1573 7

The neuropeptide head activator (HA) is a mitogen for mammalian cell lines of neuronal or neuroendocrine origin. HA signalling is mediated by a G-protein-coupled receptor (GPCR). Orphan GPCRs with homology to peptide receptors were screened for HA interaction. Electrophysiological recordings in frog oocytes and in mammalian cell lines as well as Ca(2+) mobilisation assays revealed nanomolar affinities of HA to GPR37. HA signal transduction through GPR37 was mediated by an inhibitory G protein and required Ca(2+) influx through a channel of the transient receptor potential (TRP) family. It also required activation of Ca(2+)-dependent calmodulin kinase and phosphoinositide 3-kinase. Respective inhibitors blocked HA signalling and HA-induced mitosis in GPR37-expressing cells. HA treatment resulted in internalisation of GPR37. Overexpression of GPR37 led to aggregate formation, retention of the receptor in the cytoplasm and low survival rates of transfected cells, confirming the notion that misfolded GPR37 contributes to cell death, as observed in Parkinson's disease.
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PMID:The neuropeptide head activator is a high-affinity ligand for the orphan G-protein-coupled receptor GPR37. 1644 51

To identify spinal motor neuron subtype-specific transcripts, we employed a single cell subtractive screen of mRNAs in chick embryos. We cloned a differentially expressed gene that termed spinal cord G-protein-coupled receptor 1 (SCGPR1) from its expression pattern that change dynamically in the developing spinal cord. The vertebrate orthologue of SCGPR1 is termed Gpr37 (GPCR/CNS1, ET(B)R-LP-1, Pael-R), however the specific ligand of this receptor has not been identified. Recent studies indicate that Pael-R can associate with parkin, a ubiquitin ligase which accumulates in Lewy bodies in dopaminergic neurons and is associated with Parkinson's disease. Although SCGPR1 (Gpr37) expression has been examined in adult tissues, the embryonic expression has not reported. Here, we have defined the expression pattern of SCGPR1 by in situ hybridization during chick development. SCGPR1 was first detected at HH stage 7 in the neural tube and notochord. As development progressed, SCGPR1 expression became restricted to the ventral neural tube. SCGPR1 expression was also present in the developing telencephalon, mesencephalon, retina, visceral-class motor neurons, myotome and thyroid invagination.
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PMID:Cloning and developmental expression of a chick G-protein-coupled receptor SCGPR1. 1725 Oct 65

Protease-activated receptor 1 (PAR1) is a G-protein-coupled receptor activated by serine proteases and expressed in astrocytes, microglia, and specific neuronal populations. We examined the effects of genetic deletion and pharmacologic blockade of PAR1 in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease, a neurodegenerative disease characterized by nigrostriatal dopamine damage and gliosis. After MPTP injection, PAR1-/- mice showed significantly higher residual levels of dopamine, dopamine transporter, and tyrosine hydroxylase and diminished microgliosis compared with wild-type mice. Comparable levels of dopaminergic neuroprotection from MPTP-induced toxicity were obtained by infusion of the PAR1 antagonist, BMS-200261 into the right lateral cerebral ventricle. MPTP administration caused changes in the brain protease system, including increased levels of mRNA for two PAR1 activators, matrix metalloprotease-1 and Factor Xa, suggesting a mechanism by which MPTP administration could lead to overactivation of PAR1. We also report that PAR1 is expressed in human substantia nigra pars compacta glia as well as tyrosine hydroxylase-positive neurons. Together, these data suggest that PAR1 might be a target for therapeutic intervention in Parkinson's disease.
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PMID:Exacerbation of dopaminergic terminal damage in a mouse model of Parkinson's disease by the G-protein-coupled receptor protease-activated receptor 1. 1759 74

The cyclic nucleotide phosphodiesterases (PDEs) are intracellular enzymes that catalyze the hydrolysis of 3,'5'-cyclic nucleotides, such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), to their corresponding 5'nucleotide monophosphates. These enzymes play an important role in controlling cellular concentrations of cyclic nucleotides and thus regulate a variety of cellular signaling events. PDEs are emerging as drug targets for several diseases, including asthma, cardiovascular disease, attention-deficit hyperactivity disorder, Parkinson's disease, and Alzheimer's disease. Although biochemical assays with purified recombinant PDE enzymes and cAMP or cGMP substrate are commonly used for compound screening, cell-based assays would provide a better assessment of compound activity in a more physiological context. The authors report the development and validation of a new cell-based PDE4 assay using a constitutively active G-protein-coupled receptor as a driving force for cAMP production and a cyclic nucleotide-gated cation channel as a biosensor in 1536-well plates.
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PMID:A cell-based PDE4 assay in 1536-well plate format for high-throughput screening. 1859 13

Leucine-rich repeat-containing G-protein-coupled receptor 8 (LGR8; also classified as relaxin family peptide 2 receptor; RXFP2) has been identified as a cognate receptor for the peptide hormone, insulin-like peptide 3 (INSL3) and INSL3-LGR8 signaling plays an essential role in testis descent and germ cell development in human and rodents. Lgr8 mRNA has been detected in human tissues including testis, kidney and brain, but its regional and cellular distribution in these tissues in human or other species is largely unknown. In an initial step to elucidate the physiological function of a putative INSL3-LGR8 system in rat brain, the localization of Lgr8 mRNA was investigated using in situ hybridization histochemistry, revealing a discrete distribution in forebrain, with expression highly enriched in the thalamus. High densities were detected in the parafascicular nucleus (Pf), the dorsolateral, ventrolateral and posterior thalamic nuclei, and in the medial habenula. Lgr8 transcripts were also detected in frontal and motor cortices. The comparative distribution of LGR8 (receptor protein) was examined by autoradiography of [125I]-human INSL3 binding sites, with high densities detected in the thalamus, especially in Pf, and in the entire striatum--the caudate putamen (CPmicro), islands of Calleja, olfactory tubercle, nucleus accumbens--with lower levels in distinct layers of cerebral cortex. Notably, these areas also receive dopaminergic projections. These findings demonstrate the existence of LGR8 in neuronal soma in the thalamus and axons/terminals in thalamic target areas such as the striatum and frontal cortex. LGR8 was also detected throughout the medial habenula-fasciculus retroflexus-interpeduncular nucleus pathway, further indicating that the receptor is transported from mRNA-expressing soma to remote axonal/terminal sites. These findings suggest the existence of a broadly distributed LGR8 signaling system in the rat involved in sensorimotor, limbic and cognitive functions. Further studies are now required to elucidate the precise function of LGR8, under normal and pathological conditions, as importantly, several of the equivalent receptor-positive areas in human brain are part of the pathology of neurodegenerative conditions including Parkinson's disease.
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PMID:Leucine-rich repeat-containing G-protein-coupled receptor 8 in the rat brain: Enrichment in thalamic neurons and their efferent projections. 1870 79

The orphan G-protein-coupled receptor 37 (GPR37) is a substrate of parkin, and its insoluble aggregates accumulate in brain tissue samples of Parkinson's disease patients, including Lewy bodies and neurites. Parkin activates the clearance of the unfolded receptor, while the overexpression of GPR37, in the absence of parkin, can lead to unfolded protein-induced cell death. We found that overexpression of the human GPR37 receptor in HEK293 cells and consequent activation of an endoplasmic reticulum (ER) stress response had effects comparable to starvation, in inducing the cellular autophagic pathway. Treatment with specific modulators provided further evidence for the autophagic clearance of the overexpressed GPR37 protein, in detergent-soluble and -insoluble fractions, as confirmed by the conversion of the microtubule-associated protein 1, light chain 3 (LC3)-I marker to its LC3-II isoform. Furthermore, Gpr37-null mutant mice displayed consistent alterations of ER stress and autophagic pathway markers in brain tissue samples. These findings show that GPR37 overexpression per se can induce cellular autophagy, which may prevent the selective degeneration of GPR37-expressing neurons, as reported for Parkinson's and related neurodegenerative diseases.
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PMID:Induction of macroautophagy by overexpression of the Parkinson's disease-associated GPR37 receptor. 1921 98

The activation of G-protein-coupled receptors (GPCRs) can result in the stimulation of numerous signaling networks that extend beyond canonical secondary messenger-dependent pathways. It is well-established that many of these diverse networks converge on the MAPK pathway, resulting in the activation of extracellular-signal regulated kinase 1/2 (ERK). Since the link between GPCRs and ERK can be modulated via both G-protein-dependent and -independent mechanisms, measurement of ERK phosphorylation may serve as an ideal surrogate for GPCR activation. We have combined BacMam-mediated gene delivery of the GFP-ERK2 with a time-resolved Foerster resonance energy transfer (TR-FRET) immunoassay for the measurement of intracellular phospho-ERK2 levels. Together these technologies enable a flexible platform for measuring GPCR and MAPK activation in the cell line of interest. This technology has been applied to the measurement of activation of the serotonin 5-hydroxytryptamine-1A (5-HT(1A)) receptor expressed in CHO-K1 cells. In addition to demonstrating the flexibility of this assay platform, we provide the first reported profile for 5-HT(1A) receptor-mediated ERK activation using a panel of known Parkinson's disease drugs. Our results demonstrate the value of using ERK activation as a downstream sensor for GPCR function, providing an attractive complement to upstream endpoints such as ligand occupancy and binding of GTPgammaS.
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PMID:Characterization of serotonin 5-hydroxytryptamine-1A receptor activation using a phospho-extracellular-signal regulated kinase 2 sensor. 1953 97

G-protein-coupled receptors (GPCRs) exist both as monomers and also as dimers or higher-order oligomers, representing assemblies either with their peers or with other classes of GPCR ("heterodimers"). The pharmacological profiles of heterodimers often differ from the corresponding monomers or homodimers. Heterodimerization of dopamine receptors has been shown for both the D1/D5 and D2/D3/D4 receptor families, which couple positively and negatively, respectively, to adenylyl cyclase. Notably, heterodimers are formed by: D1 and adenosine A1 receptors; D2 or D3 and adenosine A2 receptors; and D2 and somatostatin SST5 receptors. Further, D1, D2 and D3 receptors physically assemble into functional D1/D2, D1/D3 and D2/D3 heterodimers possessing binding and coupling profiles distinct from the respective monomers. This article reviews data on dopamine D3/D2 and D3/D1 heterodimers, including observations that some antiparkinsonian agents--such as the preferential high-efficacy D3 versus D2 receptor agonists, pramipexole and ropinirole--show amplified potency at D3/D2 heterodimers versus constituent monomers, and others in contrast, such as the D3/D2 receptor agonist pergolide, show no difference. This article also discusses allosteric modulation amongst heterodimeric dopamine receptors, whereby agonist actions at one member of a heterodimer influence functional coupling at the other protomer. Finally, it presents data showing that, in cells co-transfected with D3 and D1 receptors, long-term exposure to pramipexole and ropinirole (which possess negligible affinities for D1 sites) elicits supersensitivity of D1 receptor-activated adenylyl cyclase, and conversely, D3/D2 receptor agonists such as apomorphine and bromocriptine (which also act as D1 receptor agonists) do not. A hypothetical relationship between these observations and the exacerbation of gambling in Parkinson's disease by antiparkinsonian agents is discussed.
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PMID:Heterodimerization of dopamine receptors: new insights into functional and therapeutic significance. 2012 51


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