Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Autosomal dominant hypocalcemia can be caused by activating mutations of the calcium-sensing receptor (CaSR) gene. We experienced two patients (proband and her daughter) with hypocalcemia caused by a missense mutation of the CaSR gene. The proband, aged 25, showed hypocalcemia and hypoparathyroidism from infancy. She had been diagnosed as having idiopathic hypoparathyroidism and had been treated with calcitriol. She gave birth to a female infant at age 24 years. Her daughter was found to have hypocalcemia (Ca, 6.6mg/dl), without seizure or tetany, when she was 7 months old. DNA analysis of their CaSR genes showed a novel heterozygous mutation at codon 129 (TGC-to-AGC) with substitution of cysteine for serine (C129S). Familial examination revealed that this mutation had occurred de-novo in the proband. Wild-type and niutant (C129S) CaSR cDNA were transfected into HEK293 cells, and intracellular calcium concentrations were measured with a fluorescent calcium indicator. HEK cells transfected with the C129S mutant CaSR gene showed a larger increase in intracellular calcium concentration in response to the change in the extracellular calcium concentration than HEK cells transfected with the wild-type receptor. We conclude that the C129S mutation in the CaSR gene observed in these patients causes autosomal dominant hypocalcemia.
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PMID:A novel activating mutation (C129S) in the calcium-sensing receptor gene in a Japanese family with autosomal dominant hypocalcemia. 1128 19

The gamma-aminobutyric acid type A (GABA(A)) receptor mediates fast inhibitory synaptic transmission in the CNS. Dysfunction of the GABA(A) receptor would be expected to cause neuronal hyperexcitability, a phenomenon linked with epileptogenesis. We have investigated the functional consequences of an arginine-to-glutamine mutation at position 43 within the GABA(A) gamma(2)-subunit found in a family with childhood absence epilepsy and febrile seizures. Rapid-application experiments performed on receptors expressed in HEK-293 cells demonstrated that the mutation slows GABA(A) receptor deactivation and increases the rate of desensitization, resulting in an accumulation of desensitized receptors during repeated, short applications. In Xenopus laevis oocytes, two-electrode voltage-clamp analysis of steady-state currents obtained from alpha(1)beta(2)gamma(2) or alpha(1)beta(2)gamma(2)(R43Q) receptors did not reveal any differences in GABA sensitivity. However, differences in the benzodiazepine pharmacology of mutant receptors were apparent. Mutant receptors expressed in oocytes displayed reduced sensitivity to diazepam and flunitrazepam but not the imidazopyridine zolpidem. These results provide evidence of impaired GABA(A) receptor function that could decrease the efficacy of transmission at inhibitory synapses, possibly generating a hyperexcitable neuronal state in thalamocortical networks of epileptic patients possessing the mutant subunit.
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PMID:Altered kinetics and benzodiazepine sensitivity of a GABAA receptor subunit mutation [gamma 2(R43Q)] found in human epilepsy. 1241 11

We report a novel activating mutation (E604K) of the calcium-sensing receptor in a family with autosomal dominant hypocalcemia. Whereas all affected individuals exhibited marked hypocalcemia, some cases with untreated hypocalcemia exhibited seizures in infancy, whereas others were largely asymptomatic from birth into adulthood. The missense mutation E604K (G2182A; GenBank accession no. U20759), which affects an amino acid residue in the C terminus of the cysteine-rich domain of the extracellular head, cosegregated with hypocalcemia in all seven individuals for whom DNA was available. Two unaffected, normocalcemic members of the family did not exhibit the mutation. The molecular impact of the mutation on two key components of the signaling response was assessed in HEK-293 cells transiently transfected with cDNA corresponding to either the wild-type calcium-sensing receptor or the E604K mutation derived by site-directed mutagenesis. There was a significant leftward shift in the concentration response curves for the effects of extracellular Ca(2+) on both intracellular Ca(2+) mobilization (determined by aequorin luminescence) and MAPK activity (determined by luciferase expression). The C terminus of the cysteine-rich domain of the extracellular head may normally act to suppress receptor activity in the presence of low extracellular Ca(2+) concentrations.
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PMID:Autosomal dominant hypocalcemia: a novel activating mutation (E604K) in the cysteine-rich domain of the calcium-sensing receptor. 1257 88

We have previously shown that, in HEK 293 cells, overexpression of acidic calponin, an actin-binding protein, induces remodeling of actin filaments, leading to a change in cell morphology. In addition, this protein is found in dendritic spines of adult hippocampal neurons. We hypothesized that this protein plays a role in regulating actin-based filaments during dendritic spine plasticity. To assess this hypothesis, the pilocarpine model of temporal lobe epilepsy was selected because an important reorganization of the glutamatergic network, which includes an aberrant sprouting of granule cell axons, neo-synaptogenesis, and dendritic spine remodeling, is well established in the dentate gyrus. This reorganization begins after the initial period of status epilepticus after pilocarpine injection, during the silent period when animals display a normal behavior, and reaches a plateau at the chronic stage when the animals have developed spontaneous recurrent seizures. Our data show that the intensity of immunolabeling for acidic calponin was clearly increased in the inner one-third of the molecular layer of the dentate gyrus, the site of mossy fiber sprouting, and neo-synaptogenesis, at 1 and 2 weeks after pilocarpine injection (silent period) when the reorganization was taking place. In contrast, in chronic pilocarpine-treated animals, when the reorganization was established, the levels of labeling for acidic calponin in the inner molecular layer were similar to those observed in control rats. In addition, double immunostaining studies suggested that the increase in acidic calponin levels occurred within the dendritic spines. Altogether, these results are consistent with an involvement of acidic calponin in dendritic spine plasticity.
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PMID:Increased levels of acidic calponin during dendritic spine plasticity after pilocarpine-induced seizures. 1462 Aug 80

Galanin, a 29- or 30-amino acid neuropeptide, has been implicated in the modulation of seizures. In this study, we constructed a recombinant adeno-associated viral (AAV) vector to constitutively over-express galanin (AAV-GAL). The vector mediated efficient transduction of HEK 293 cells in vitro and robust galanin expression in vivo when injected into the rat dorsal hippocampus. Rats were administered kainic acid intrahippocampally 2.5 months following AAV-GAL or empty vector (AAV-Empty) injection to study the effect of vector-mediated galanin over-expression on seizures. AAV-GAL-injected rats showed a decreased number of seizure episodes and total time spent in seizures compared to AAV-Empty rats, despite similar latencies to development of the first EEG seizure and similar levels of neuronal damage in the CA3 region for both groups. These data show that recombinant AAV mediates strong and stable over-expression of galanin when injected into the rat hippocampus resulting in a significant anticonvulsive effect. The seizure suppression effect of galanin expression in the hippocampus by viral vectors may lead to novel therapeutic strategies for the treatment and management of intractable seizures with focal onset such as temporal lobe epilepsy.
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PMID:Recombinant AAV-mediated expression of galanin in rat hippocampus suppresses seizure development. 1462 42

A genetic component is associated with the development of many forms of epilepsy. Recently, mutations in the GABAA receptor have been linked to several inherited epilepsies. One of these mutations is a non-conservative change of alanine to aspartate in the third transmembrane domain of the alpha1 subunit. To determine the functional consequences of this alteration, mutated alpha subunits were transiently transfected along with wild-type beta3 and gamma2L subunits into HEK-293T cells. The mutated alpha1(A294D) subunit reduced GABA sensitivity of the receptor, increased the deactivation rate and slowed desensitization. The mutation caused a reduction in channel open time but no change in single channel conductance. Studies with additional mutants, altering the charge and/or size of the side-chain, indicated that both size and hydrophobicity of the residue at this location influence channel gating. The effects on GABA sensitivity, deactivation rate and channel open time are consistent with a reduced efficacy of channel gating, and would be expected to decrease GABAergic neurotransmission. The alpha1 subtype is the most widely expressed of the alpha subunits, with expression increasing throughout development. Therefore, production of the mutated subunit could cause global hyperexcitability throughout the brain, leading to generalized seizures with juvenile onset.
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PMID:A mutation in the GABAA receptor alpha 1 subunit linked to human epilepsy affects channel gating properties. 1499 40

The purpose of this work was to develop a gene delivery system that expressed acetylcholinesterase (AChE) for prolonged periods. An adeno-associated virus (AAV) expressing human AChE was constructed by co-transfecting three plasmids into HEK 293T cells. The purified vector expressed 0.17 microg AChE per 1 million viral particles in culture medium in 23 h, or 0.8 U/ml. The AAV/hAChE was injected into muscle of adult AChE knockout mice and into the brains of 3-6 week old AChE knockout mice. Intramuscular injection yielded plasma AChE levels approaching 50% of the AChE activity of wild-type mouse plasma. The highest AChE activity was found on day 3 post-injection. AChE activity declined thereafter to a constant 7% of normal. The decreased level was accompanied by the appearance of anti-human AChE antibodies, suggesting partial clearance of AChE from plasma by antibodies. Intrastriatal injection resulted in AChE expression in the striatum. No antibodies were detected in animals treated intrastriatally. Motor coordination was improved and the lifespan of intrastriatally-treated AChE knockout mice was prolonged. Human AChE was expressed in mouse brain for up to 7 months after intrastriatal injection of an AAV/hAChE construct. Gene-therapy to supply AChE to the striatum improved motor coordination and prolonged the life of mice genetically deficient in AChE, probably by reducing their susceptibility to spontaneous seizures. This supports the hypothesis that their seizures are induced by excess acetylcholine.
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PMID:Delivery of human acetylcholinesterase by adeno-associated virus to the acetylcholinesterase knockout mouse. 1624 6

The groggy rat (strain name; GRY) exhibits ataxia, an unstable gait, and paroxysmal severe extension of the entire body. Adults show a reduction in size of the cerebellum and presynaptic and axon terminal abnormalities of Purkinje cells. These neurological abnormalities are inherited in an autosomal recessive manner, and the causative mutation has been named groggy (gry). In this study, we mapped gry on rat chromosome 19 and found a nonconservative missense (M251K) mutation in the alpha(1A) subunit of the P/Q-type voltage-gated Ca(2+) channel gene (Cacna1a) within the gry-critical region. This mutation was located at a highly conserved site close to the ion-selective pore and led to the shortening of the inactivation phase of the Ca(2+) channel current without a change of peak current density or current-voltage relationship in whole cell patch recordings of the recombinant Ca(2+) channel expressed in HEK cells. It has been well established that mice with a mutation at Cacna1a such as tottering and leaner show absence seizures. The Cacna1a-mutant GRY rat also exhibited absence-like seizures from 6 to 8 weeks of age, which were characterized by bilateral and synchronous 7-8 Hz spike-and-wave discharges concomitant with sudden immobility and staring, on cortical and hippocampal EEGs. The pharmacological profile of the seizures was similar to that of human absence epilepsy: the seizures were inhibited by ethosuximide and valproic acid but not phenytoin. Thus, the GRY rat with P/Q-type Ca(2+) channel disorders is a useful model for studying absence epilepsy and Cacna1a-related diseases.
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PMID:The ataxic groggy rat has a missense mutation in the P/Q-type voltage-gated Ca2+ channel alpha1A subunit gene and exhibits absence seizures. 1719 42

Acidosis is a common feature of neurological conditions including brain ischemia, epileptic seizures, and neurotrauma. Activation of Ca(2+)-permeable acid-sensing ion channels (ASIC1a) is involved in acidosis-mediated ischemic brain injury. Zn(2+) is a divalent cation concentrated in nerve terminals in various brain regions, and is released into the extracellular space during excitatory stimulation. Our previous studies have demonstrated that the activities of ASIC1a containing channels and acid-induced increased intracellular Ca(2+) concentrations are inhibited dramatically by the physiological concentration of extracellular Zn(2+). In this report, we demonstrate that decreasing the concentration of the extracellular Zn(2+) significantly enhances acid-induced injury of HEK 293 cells, a cell line expressing homomeric ASIC1a-like channels, whereas increasing the concentration of extracellular Zn(2+) appears to be protective. Although increased concentrations of intracellular Zn(2+) have been shown to be detrimental to neurons, our findings may suggest that the physiological concentration of extracellular Zn(2+) might play a protective role in acidosis-induced, ASIC1a-mediated neuronal injury.
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PMID:Extracellular zinc protects against acidosis-induced injury of cells expressing Ca2+-permeable acid-sensing ion channels. 1726 12

Baicalin, a naturally occurring flavonoid, was previously reported to induce anxiolytic-like effect devoid of sedation and myorelaxation in mice, acting through type A gamma-aminobutyric acid (GABA(A)) receptor benzodiazepine (BZ) site. The present study further expanded the behavioral pharmacology profile of baicalin and subtype selectivity was explored as a possible mechanism underlying its in vivo effects on mice. Baicalin was characterized using convulsion, memory, and motor function related animal tests; and its selectivity towards recombinant GABA(A) receptor subtypes expressed in HEK 293T cells was determined by radioligand binding assay and electrophysiological studies. In the picrotoxin-induced seizure, step-through passive avoidance and rotarod tests, the anticonvulsant, amnesic and motor incoordination effects commonly associated with classical BZs were not observed when baicalin was administered at effective anxiolytic doses, demonstrating a separation of the anticonvulsant, amnesic and motor incoordination effects from the anxiolytic-like effect. Although baicalin exhibited higher binding affinity for the alpha1-containing GABA(A) subtype compared with alpha2-, alpha3-, and alpha5-containing subtypes, this was not statistically significant. In contrast to the classical BZ diazepam, baicalin showed significant preference for alpha2- and alpha3-containing subtypes compared to alpha1- and alpha5-containing subtypes in whole-cell patch clamp studies (P < 0.01). Its subtype selectivity suggested that baicalin exerted its in vivo anxiolytic-like effect mainly through the alpha2- and alpha3-containing subtypes. Therefore, the present study revealed an underlying mechanism for the selective anxiolytic profile of baicalin, suggesting alpha2- and alpha3-containing subtypes were important drug targets for flavonoid-based anxiolytics.
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PMID:GABA A receptor subtype selectivity underlying selective anxiolytic effect of baicalin. 1872 37


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