Cacnb4

..The activity-dependent shuttling of beta(4b) into and out of the nucleus indicates a specific role of this beta subunit in neurons, in communicating the activity of calcium channels to the nucleus...

..The hypothesis of an adaptive glial mechanism, relating to the age-dependent decrease of seizure susceptibility in DBA/2 mice, is postulated...

..In the current studies, the anatomical basis for paroxysmal dyskinesias in lethargic mice was determined via histochemical methods sensitive to changes in regional brain activity followed by ..

..Nimodipine diminished the LP, leading us to survey VDCC beta-subunit mutant mice. Lethargic mice, which harbor a loss of function mutation in the beta4 subunit of VDCCs, exhibited a significant shift in ..

..Although Cav1 channels of lymphocytes retain their voltage dependency, T cell receptor stimulation dramatically increases channel opening, providing a new mechanism for calcium entry in lymphocytes...

..We used a positional candidate approach to determine that the ataxia and seizures in the lethargic (lh) mouse arise from mutation of the beta-subunit gene Cchb4 on mouse chromosome 2...

..The mouse mutant lethargic (lh) exhibits severe neurological defects due to a mutation that deletes the alpha1 subunit interaction domain ..

..The purpose of this study was to dentify which of the four beta subunits of VDCCs participates in the formation of this channel at the photoreceptor synapse and to determine how its absence affects visual processing...

..These findings suggest that beta subunits might play a major role in conferring calcium handling heterogeneity within the developing embryonic myocardium, while alpha1C subunits might contribute just transiently...

..Furthermore, mRNA of these beta-subunits is strongly expressed in dorsal root ganglion neurons, which have many voltage-dependent calcium channels...

b>Lethargic mutant mice carry a mutation in the CCHB4 gene, which encodes the beta4 subunit of voltage-regulated calcium channels...

..1/alpha1A subunit), lethargic (lh; beta4 subunit), and stargazer (stg; gamma2 subunit) brain slices...

..The development of pharmaceuticals directed towards specific epilepsy genotypes can be anticipated, and the introduction of patient mutations into the mouse genome will provide models for testing these targeted therapies...

..Since epilepsy is assumed to be a disease syndrome which is probably manifested by abnormal expression of multifocal genes, determination of the role of each chromosomal locus in the provocation of seizure activity is important...

..release at hippocampal Schaffer collateral synapses in both tottering (tg, alpha(1A) subunit) and lethargic (lh, beta(4) subunit) mutant mice...

..The tottering (tg) locus encodes the calcium channel alpha1 subunit gene Cacna1a, lethargic (lh) encodes the beta subunit gene Cacnb4, and stargazer (stg) encodes the gamma subunit gene Cacng2...

..Here we summarize the phenotype of mice deficient in the beta1 subunit, the beta3 subunit or the beta4 subunit, respectively...

..Then, from the new wave of genetic and functional studies of these mutants we discuss their prospects for yielding insight into the molecular mechanisms of epilepsy...

..e., lethargic (beta4(lh/lh)), tottering (alpha1A(tg/tg)), or stargazer (gamma2(stg/stg))...

..Because acute lung injury is a sporadic disease produced by heterogeneous precipitating factors, previous genetic analyses are mainly limited to candidate gene case-control studies...

..An NMR-based two-site docking model of β4c in complex with dimerized CSD is presented. Possible roles for the interaction are discussed...

..Developmental changes are likely determined by an intrinsic program and not regulated by changes in neuronal activity...

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..These results identify an apparently common cellular pathology in typical absence seizures that may have epileptogenic importance and highlight potential therapeutic targets for the treatment of absence epilepsy...

..These results indicate that neither Ca(V)beta3 nor Ca(V)beta4 are indispensable for hair cell Ca(2+) currents but contribute to the overall current properties...

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..Thus, we reveal a novel function for a cell adhesion molecule in coordination of cell behavior with intracellular phosphatase activity...

..Moreover, our work has revealed that many of the genes expressed in cortical interneuron precursors have been independently linked to neurological disorders in both mice and humans...

..Ducky, lethargic and stargazer are mutant mice that lack functional alpha(2)delta-2, beta(4) and gamma(2) accessory Ca(v) channel ..

..These observations suggest that the Cav channels expressed by T cells have adopted novel regulation/gating mechanisms...

..The lethargic mouse has been shown to be due to mutations in the gene encoding another calcium channel subunit, beta4...

..In this study, we examined the relationship between Cacnb4 and GABA(B) receptor mRNA expression in brains from Cacnb4lh homozygotes and (+/+) controls...

..These findings suggest that there may be more human transcripts than currently recognized. The possible involvement of the new growing family of Tmpo proteins in nuclear architecture and cell cycle control is discussed...

This study begins to explore possible mechanisms underlying the role of GABAB receptors in absence seizures in lethargic (lh/lh) mice...

..we have shown a significant increase in number of GABAB receptor binding sites in neocortex and thalamus of lethargic (lh/lh) mice, a mutant strain exhibiting absence seizures...

..In this study we measured the antiabsence effects of SCH 50911 in three animal models: the lethargic (lh/lh) mutant mouse, which has spontaneous absence seizures; and two rat models in which absence seizures were ..

..The alpha 1, beta 2, and beta 4 subunit genes, termed Cchna1, Cchb2, and Cchb4, are located at different sites on proximal Chr 2, while the beta 3 subunit gene Cchb3 maps to Chr 15 near Wnt1...

In previous work we have shown that GABAB receptors are required for expression of absence seizures in the lethargic (lh/lh) mouse model; that lh/lh mice have increased numbers of GABAB binding sites compared to nonepileptic littermates (..

b>Lethargic (lh/lh) mice, which function as an animal model of absence seizures, have spontaneous seizures that have behavioral and electrographic features and anticonvulsant sensitivity similar to those of human absence seizures...

In a series of recent studies on 'lethargic' mice, a neurological mutation of the mouse, significant abnormalities were discovered in the thymus and its dependent regions in the lymph nodes and spleen...

..The current evidence and interpretations of this work are presented here...

T cell function of "lethargic" mutant mice which exhibit spontaneous thymic involution was evaluated by skin transplantation and graft-versus-host reaction tests...

..These data suggest that GABA-synthesis is maintained or increased in NRT neurons in the Cacnb4lh mouse model...

The mutated gene in the lethargic (Cacnb4lh) mouse model of absence seizures encodes the beta4 subunit of voltage-gated calcium channels (VGCCs), leading to decreased mRNA expression of a beta4 subunit that is truncated and cannot bind ..

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Excitatory but not inhibitory synaptic transmission is reduced in lethargic (Cacnb4(lh)) and tottering (Cacna1atg) mouse thalami...

..AMP responsive element (CRE)- and activator protein 1 (AP-1) DNA-binding activities in various brain regions of lethargic (lh/lh) mice, a genetic model of absence seizures...

..The focus of this study is the expression and assembly of alpha1B and beta isoforms in the epileptic mouse, lethargic (lh/lh), a mutant anticipated to produce a truncated beta4 subunit (Burgess, D. L., Jones, J. M., Meisler, M. H...

..This difference between the species appears to result from an absence of a functional macrophage-specific promoter in mice...

The mouse neurological mutant lethargic (lh) is characterized by ataxia, focal myoclonus, and absence epilepsy due to a loss-of-function mutation in the beta4 subunit of the voltage-gated calcium channel...

..have been identified by positional cloning of the spontaneous mouse mutants motor endplate disease, tottering, lethargic and weaver...

..of generalized absence seizures in three mouse models: two mutant strains with spontaneous absence seizures, lethargic and stargazer, and ddY mice (GHB model) in which absence seizures were induced by administering gamma-..

..These data help to explain the different response characteristics of two closely related early response genes, Nurr1 and Nur77...

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..The interaction between Scn8a and Scnm1 is a model for gene interactions that modify human susceptibility to inherited neurological disorders. ..

..We propose to extend this work to related genes and disorders, and to generate better animal models of the human disease in order to understand the pathogenic mechanism and provide an accurate model for testing therapeutic intervention. ..

..This project will characterize the neurological and behavioral effects of specific changes in sodium channel genes, using mouse models of human mutations. ..

..This project will characterize the neurological and behavioral effects of specific changes in sodium channel genes, using mouse models of human mutations. ..

..This project will characterize the neurological and behavioral effects of specific changes in sodium channel genes, using mouse models of human mutations. ..

..The GTP is one of the oldest and largest NIH-supported training programs, and continues to be a vital component of graduate education and biomedical research at the University of Michigan. ..

..Because of the high level of alternative splicing in the nervous system, variation in SCNM1 may be of particular significance for neurological disease. ..

..This work will extend our knowledge of the physiological and cellular functions of SCN8A in the CNS and PNS and its role in neurological disease. ..

..These projects will contribute to isolation of genes involved in craniofacial development, identification of new genetic disorders, and development of the human and mouse comparative genetic maps. ..

..These investigations will contribute to our understanding of the molecular basis of tissue-specific and hormonal regulation of mammalian gene expression...

..Insertional mutation in transgenic mice provides a powerful system for the identification and genetic mapping of new functional elements in the mammalian genome, and for molecular characterization of these new genes...

..If we can understand how normal enzyme concentration is altered by mutation, the regulatory mechanisms responsible for maintenance of steady-state enzyme levels may be identified. ..

..Promoter function will also be assayed in transgenic mice. This work will provide thorough characterization of normal and mutated forms of a novel sodium channel and contribute to the diagnosis and treatment of neuromuscular disease. ..

..The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page 1 Description, ..

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