Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mas proto-oncogene encodes a seven membrane-spanning G-protein-coupled receptor which is activated by angiotensins. In the postnatal and adult rat, mas mRNA is specifically expressed at high levels in hippocampal neurons. We report here using in situ hybridization and RNase protection that brief seizure episodes lead to a significant and transient increase in mas mRNA in the hippocampus. Increased levels of mas transcripts were detected 2, 4, and 6 h following seizure. By 24 h post seizure, baseline levels were detected. The presumed subsequent increase of the mas receptor protein may contribute to anatomical and physiological plasticity that is associated with intense activation of hippocampal pathways.
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PMID:Expression of the mas proto-oncogene in the rat hippocampal formation is regulated by neuronal activity. 823 33

Neuropeptide Y receptors belong to the G-protein-coupled receptor superfamily and mediate a wide variety of physiological functions, including blood pressure regulation, hormone release, appetite control, seizure propensity, cognition, and emotion. The recent description of a new neuropeptide Y receptor, Y5, expressed in hypothalamic nuclei in rat brain, raised the possibility that Y5 was the receptor mediating the feeding and appetite-related functions of neuropeptide Y. This was supported by subsequent data showing a downregulation of this "feeding" receptor in the brain of the obese Zucker rat (Widdowson, 1997). We have performed a detailed analysis of Y5 expression in rat brain using in situ hybridization histochemistry with digoxygenin-labeled riboprobes and compared this to expression of Y5 in human brain regions. mRNA for the human Y5 receptor was highly expressed in human hypothalamic and thalamic nuclei. In particular, the arcuate and paraventricular nuclei of the hypothalamus, midline thalamic nuclei, and amygdala showed very high levels of expression with high levels in hippocampus. The striking conservation of expression of the rat and human Y5 receptors in relevant hypothalamic and other nuclei implies sharing of a major neuroendocrine functional role by this receptor.
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PMID:Conservation of expression of neuropeptide Y5 receptor between human and rat hypothalamus and limbic regions suggests an integral role in central neuroendocrine control. 1057 27

Melanin-concentrating hormone (MCH), a 19 amino acid cyclic peptide, is largely expressed in the hypothalamus. It is implicated in the control of general arousal and goal-orientated behaviours in mammals, and appears to be a key messenger in the regulation of food intake. An understanding of the biological actions of MCH has been so far hampered by the lack of information about its receptor(s) and their location in the brain. We recently identified the orphan G-protein-coupled receptor SLC-1 as a receptor for the neuropeptide MCH. We used in situ hybridization histochemistry and immunohistochemistry to determine the distribution of SLC-1 mRNA and its protein product in the rat brain and spinal cord. SLC-1 mRNA and protein were found to be widely and strongly expressed throughout the brain. Immunoreactivity was observed in areas that largely overlapped with regions mapping positive for mRNA. SLC-1 signals were observed in the cerebral cortex, caudate-putamen, hippocampal formation, amygdala, hypothalamus and thalamus, as well as in various nuclei of the mesencephalon and rhombencephalon. The distribution of the receptor mRNA and immunolabelling was in good general agreement with the previously reported distribution of MCH itself. Our data are consistent with the known biological effects of MCH in the brain, e.g. modulation of the stress response, sexual behaviour, anxiety, learning, seizure production, grooming and sensory gating, and with a role for SLC-1 in mediating these physiological actions.
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PMID:The distribution of the mRNA and protein products of the melanin-concentrating hormone (MCH) receptor gene, slc-1, in the central nervous system of the rat. 1076 50

Until recently, all genes found to be mutated in hereditary idiopathic epilepsies encoded subunits of ion channels, leading to the view of this class of diseases as channelopathies. Two apparent exceptions to this rule are the MASS1 gene, which is mutated in the Frings mouse model of audiogenic epilepsy, and the LGI1 gene, which is mutated in autosomal dominant partial epilepsy with auditory features (ADPEAF). Careful sequence analysis of the two protein products encoded by those genes shows a common feature: both sequences harbour a novel homology domain consisting of a 7-fold repeated 44-residue motif. The architecture and structural features of this new domain make it a likely member of the growing class of protein interaction domains with a seven-bladed beta-propeller fold. In the MASS1 gene product, which has recently been shown to be a fragment of the very large G-protein-coupled receptor VLGR1, this EAR domain (for epilepsy-associated repeat) is part of the ligand-binding ectodomain. LGI1, as well as a number of newly identified LGI1 relatives, is predicted to be a secreted protein, and consists of an N-terminal leucine-rich repeat region and a C-terminal EAR region. The known portion of the human genome encodes six EAR proteins, some of which map to chromosome regions associated with seizure disorders. The EAR domain is likely to play an important role in the pathogenesis of epilepsy, either by binding to an unknown anti-epileptic ligand, or more likely by interfering with axon guidance or synaptogenesis.
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PMID:A common protein interaction domain links two recently identified epilepsy genes. 1209 17

The catecholamines norepinephrine and dopamine are abundant in the CNS, and modulate neuronal excitability via G-protein-coupled receptor signaling. This review covers the history of research concerning the role of catecholamines in modulating seizure susceptibility in animal models of epilepsy. Traditionally, most work on this topic has been anatomical, pharmacological, or physiological in nature. However, the recent advances in transgenic and knockout mouse technology provide new tools to study catecholamines and their roles in seizure susceptibility. New results from genetically engineered mice with altered catecholamine signaling, as well as possibilities for future experiments, are discussed.
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PMID:The role of catecholamines in seizure susceptibility: new results using genetically engineered mice. 1211 99

Neuropeptide Y (NPY) is a 36-amino-acid peptide that exhibits a large number of physiological activities in the central and peripheral nervous systems. NPY mediates its effects through the activation of six G-protein-coupled receptor subtypes named Y(1), Y(2), Y(3), Y(4), Y(5), and y(6). Evidence suggests that NPY is involved in the pathophysiology of several disorders, such as the control of food intake, metabolic disorders, anxiety, seizures, memory, circadian rhythm, drug addiction, pain, cardiovascular diseases, rhinitis, and endothelial cell dysfunctions. The synthesis of agonists and antagonists for these receptors could be useful to treat several of these diseases.
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PMID:Neuropeptide Y and its receptors as potential therapeutic drug targets. 1241 94

At approximately 6300 amino acids, very large G-protein-coupled receptor-1 (VLGR1, also termed Mass1) is the largest known cell surface protein. It is expressed at high levels within the embryonic nervous system, especially the ventricular zone. A naturally occurring nonsense mutation in VLGR1, V2250X, is linked with susceptibility to audiogenic seizures in mice. Interpretation of this finding is complicated by the existence of splice and transcriptional variants. We targeted the transmembrane and cytoplasmic domains of VLGR1, yielding a gene encoding the complete ectodomain of VLGR1 fused to antigenic tags (VLGR/del7TM). Homozygous mutant mice are susceptible to audiogenic seizures. Western blots detect a single very high molecular weight protein in brain extracts from VLGR/del7TM mice. These findings suggest that loss of VLGR1 transmembrane and cytoplasmic domains underlies the seizure phenotype in both mutant mouse strains, perhaps by disrupting signals regulating neural development.
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PMID:Loss of the transmembrane and cytoplasmic domains of the very large G-protein-coupled receptor-1 (VLGR1 or Mass1) causes audiogenic seizures in mice. 1520 56

Activation of the cannabinoid type 1 (CB1) receptor, a major G-protein-coupled receptor in brain, acts to regulate neuronal excitability and has been shown to mediate the anticonvulsant effects of cannabinoids in several animal models of seizure, including the rat pilocarpine model of acquired epilepsy. However, the long-term effects of status epilepticus on the expression and function of the CB1 receptor have not been described. Therefore, this study was initiated to evaluate the effect of status epilepticus on CB1 receptor expression, binding, and G-protein activation in the rat pilocarpine model of acquired epilepsy. Using immunohistochemistry, we demonstrated that status epilepticus causes a unique "redistribution" of hippocampal CB1 receptors, consisting of specific decreases in CB1 immunoreactivity in the dense pyramidal cell layer neuropil and dentate gyrus inner molecular layer, and increases in staining in the CA1-3 strata oriens and radiatum. In addition, this study demonstrates that the redistribution of CB1 receptor expression results in corresponding functional changes in CB1 receptor binding and G-protein activation using [3H] R+-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl](1-napthalen-yl)methanone mesylate (WIN55,212-2) and agonist-stimulated [35S]GTPgammaS autoradiography, respectively. The redistribution of CB1 receptor-mediated [35S]GTPgammaS binding was 1) attributed to an altered maximal effect (Emax) of WIN55,212-2 to stimulate [35S]GTPgammaS binding, 2) reversed by the CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A), 3) confirmed by the use of other CB1 receptor agonists, and 4) not reproduced in other G-protein-coupled receptor systems examined. These results demonstrate that status epilepticus causes a unique and selective reorganization of the CB1 receptor system that persists as a permanent hippocampal neuronal plasticity change associated with the development of acquired epilepsy.
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PMID:Status epilepticus causes a long-lasting redistribution of hippocampal cannabinoid type 1 receptor expression and function in the rat pilocarpine model of acquired epilepsy. 1743 56

GPR56, a member of the G-protein-coupled receptor family, plays a role in the formation of the frontal and parietal brain lobes and cortical lamination in the embryonic stage. A recent report indicated the existence of GPR56 transcripts in the subventricular zone (SVZ) and hippocampal subgranular zone (SGZ) of the adult mouse brain. Both these regions are known to continually produce neural progenitor cells in the adult brain. Here, we demonstrate abundant GPR56 protein expression in the ependymal cell layer and SVZ as well as its reciprocal translational regulation by a 12-day behavioral stress paradigm and 10-day electroconvulsive seizure (ECS) treatment. Our study revealed that GPR56 transcript expression in the hippocampus was regulated by stress and seizure in a manner identical to that in the SVZ. GPR56 expression was downregulated by stress and upregulated by the ECS treatment in both regions, whereas nestin expression showed no changes. Western blot analysis revealed a robust ECS-induced increase in brain-derived neurotrophic factor expression in the wall of the lateral ventricle including the ependymal cell layer and the SVZ, which may provide a possible regulatory mechanism for GPR56 expression. We consider that GPR56 is expressed in the ependymal cell layer and in immature progenitor cells and that its expression is regulated by functional stimulation.
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PMID:Stress and electroconvulsive seizure differentially alter GPR56 expression in the adult rat brain. 1794

Mutations in GPR56, an orphan G-protein-coupled receptor (GPCR), cause bilateral frontoparietal polymicrogyria (BFPP), a disorder characterized by mental retardation, seizures, motor developmental delay, and ataxia. BFPP patients have structural abnormalities of the cerebral cortex, cerebellum, and pons. To shed light on the function of GPR56 and the anatomical and behavioral defects underlying BFPP, we analyzed the cerebellum of mice lacking this GPCR. Gpr56(-/-) mice display a severe malformation of the rostral cerebellum that develops perinatally. Defects involve fusion of adjacent lobules, disrupted layering of neurons and glia, and fragmentation of the pial basement membrane. At the age of defect onset, GPR56 expression is restricted specifically to developing granule cells in the rostral cerebellum, suggesting that GPR56 regulates properties of these cells. Indeed, granule cells from the rostral region of perinatal Gpr56(-/-) cerebella show loss of adhesion to extracellular matrix molecules of the pial basement membrane. Interference RNA-mediated knockdown of GPR56 recapitulates the loss of adhesion seen in knock-outs, and reexpression of GPR56 rescues the adhesion defect in knock-out granule cells. Loss of GPR56 does not affect cell proliferation, migration, or neurite outgrowth. These studies establish a novel role for GPR56 in the adhesion of developing neurons to basal lamina molecules and suggest that this adhesion is critical for maintenance of the pia and proper cerebellar morphogenesis.
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PMID:GPR56-regulated granule cell adhesion is essential for rostral cerebellar development. 1951 12


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