Low level expression of glycine receptor beta subunit transgene is sufficient for phenotype correction in spastic mice.

Hartenstein, Bettina; Schenkel, Johannes; Kuhse, Jochen; Besenbeck, Birgit; Kling, Claudia; Becker, Cord‐Michael; Betz, Heinrich; Weiher, Hans

doi:10.1002/j.1460-2075.1996.tb00469.x

Cited by 40 publications

(44 citation statements)

References 46 publications

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“…Similarly, the spastic and spasmodic mice have a myoclonic phenotype and mutations within glycine receptor genes; spasmodic mice have point mutations in GlyR ␣1, and spastic mice have splicing defects due to transposable element insertion within a splice junction of GlyR 2B (49,50). In addition, expression of a wild-type GlyR 2B transgene in spastic mice rescues the myoclonic phenotype (26). These observations suggest the possibility that the neurologic disease in POMA results from aberrant regulation of glycine receptor expression.…”

Section: Discussionmentioning

confidence: 91%

The Neuronal RNA Binding Protein Nova-1 Recognizes Specific RNA Targets In Vitro and In Vivo

Buckanovich

Darnell

1997

Molecular and Cellular Biology

246

254

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Nova-1, an autoantigen in paraneoplastic opsoclonus myoclonus ataxia (POMA), a disorder associated with breast cancer and motor dysfunction, is a neuron-specific nuclear RNA binding protein. We elements were identified in two neuronal pre-mRNAs, one encoding the inhibitory glycine receptor ␣2 (GlyR ␣2) and a second encoding Nova-1 itself. Nova-1 protein binds these RNAs with high affinity and specificity in vitro, and this binding can be blocked by POMA antisera. Moreover, both Nova-1 and GlyR ␣2 pre-mRNAs specifically coimmunoprecipitated with Nova-1 protein from brain extracts. Thus, Nova-1 functions as a sequence-specific nuclear RNA binding protein in vivo; disruption of the specific interaction between Nova-1 and GlyR ␣2 pre-mRNA may underlie the motor dysfunction seen in POMA.RNA-protein interactions are important in the posttranscriptional regulation of RNA metabolism and expression. Nascent RNA transcripts associate with large multiprotein complexes that include hnRNP proteins and snRNP particles (19). RNA protein complexes subsequently participate in polyadenylation, RNA splicing, RNA transport, and translational control. Defining target RNAs with which RNA binding proteins (RBPs) interact has been critical in defining their function. In Drosophila melanogaster, the identification of sequence-specific targets for the sex-lethal (sxl) (5, 30) and transformer-2 (28) RBPs has led to a precise understanding of their role in regulating RNA splicing. In mammals, the ability of U2AF(65) to bind to polypyrimidine tracts is believed to recruit U2 snRNP to the branch site (48, 69). Identification of specific RNA ligands for the human immunodeficiency virus Rev and Tat proteins has clarified their role in regulating viral RNA transcription, processing, and transport (14,27,34,40,70). There remain, however, many RBPs for which specific RNA targets have not been identified.RNA selection has been used as an in vitro approach to identify RNA ligands for RBPs (61,65). This approach was originally used to confirm the specificity of rRNA binding sites recognized by T4 DNA polymerase (65) and has subsequently been used to confirm and extend known binding sites for the U1-snRNP-A protein (64), sxl (55), and the viral Rev (3, 31) and Tat (66) proteins. RNA selection experiments have also been used in efforts to identify RNA ligands for RBPs that do not have known sequence-specific binding sites, including hnRNP proteins (12), SR proteins (29, 62), and the neuronal RBP (n-RBP) Hel-N1 (36), although in general these studies have yielded short in vitro consensus RNA ligands whose in vivo significance is currently being explored.Nova-1 is a nuclear n-RBP identified as a target antigen in paraneoplastic opsoclonus myoclonus ataxia (POMA) (9, 10,

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Section: Discussionmentioning

confidence: 91%

The Neuronal RNA Binding Protein Nova-1 Recognizes Specific RNA Targets In Vitro and In Vivo

Buckanovich

Darnell

1997

Molecular and Cellular Biology

246

254

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“…Display of hindfeet clenching or limb clenching when picked up by the tail was determined. Righting time was determined after bringing the animals into a supine position as described previously (Hartenstein et al, 1996;Becker et al, 2000).…”

Section: Methodsmentioning

confidence: 99%

Spinal Antiallodynia Action of Glycine Transporter Inhibitors in Neuropathic Pain Models in Mice

Morita¹,

Motoyama²,

Kitayama³

et al. 2008

J Pharmacol Exp Ther

115

143

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Neuropathic pain is refractory against conventional analgesics, and thus novel medicaments are desired for the treatment. Glycinergic neurons are localized in specific brain regions, including the spinal cord, where they play an important role in the regulation of pain signal transduction. Glycine transporter (GlyT)1, present in glial cells, and GlyT2, located in neurons, play roles in modulating glycinergic neurotransmission by clearing synaptically released glycine or supplying glycine to the neurons and thus could modify pain signal transmission in the spinal cord. In this study, we demonstrated that i.v. or intrathecal administration of GlyT1 inhibitors, cis-N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-yl methyl)amino methylcarboxylic acid (ORG25935) or sarcosine, and GlyT2 inhibitors, 4-benzyloxy-3,or knockdown of spinal GlyTs by small interfering RNA of GlyTs mRNA produced a profound antiallodynia effect in a partial peripheral nerve ligation model and other neuropathic pain models in mice. The antiallodynia effect is mediated through spinal glycine receptor ␣3. These results established GlyTs as the target molecules for the development of medicaments for neuropathic pain. However, these manipulations to stimulate glycinergic neuronal activity were without effect during the 4 days after nerve injury, whereas manipulations to inhibit glycinergic neuronal activity protected against the development of allodynia in this phase. The results implied that the timing of medication with their inhibitors should be considered, because glycinergic control of pain was reversed in the critical period of 3 to 4 days after surgery. This may also provide important information for understanding the underlying molecular mechanisms of the development of neuropathic pain.Neuropathic pain arising from peripheral or spinal nerve injury and diabetes or infection with herpes virus is a result of the final product of an altered peripheral, spinal, and supraspinal process for which the usual analgesics are not effective and novel analgesics are desired. Recent progress of research on the underlying mechanism of the pathology revealed more complexity, depending on the cause and stage of ongoing neuropathy. Among various mechanisms involved in the pathology, alterations of synaptic transmission within the spinal cord dorsal horn as well as peripheral nerves after peripheral nerve injury play key roles. In addition to the activation of stimulatory spinal neurotransmission, disinhibition of inhibitory neurotransmission has been implicated in the generation of inflammatory and neuropathic pain (Woolf and Mannion, 1999). Glycine as well as GABA serve as major inhibitory neurotransmitters in the spinal cord of vertebrates. In fact, relief from glycinergic inhibition by an inhib-

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“…Only a minor fraction of mRNA is spliced correctly, thus allowing reduced amounts of β subunit polypeptides to be synthesized. The reduced availability of mRNAs encoding the β subunits correlates well with the reduced expression of GlyR in the central nervous system (CNS; Hartenstein et al 1996). Thus, GlyRs in the mutant spastic are functionally normal but reduced in number.…”

Section: Systemic Functionsmentioning

confidence: 97%

Glycinergic transmission

Kirsch

2006

Cell Tissue Res

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Inhibition in the mature central nervous system is mediated by activation of gamma-aminobutyric acid (GABA(A)) and glycine receptors. Both receptors belong to the same superfamily of ligand-gated ion channels and share common transmembrane topology and structural and functional features. Glycine receptors are pentameric ligand-gated anion channels composed of two different subunits, named alpha und beta, that assemble with a fixed stoichiometric ratio of two alpha to three beta subunits. Four genes encoding the alpha subunits exist, whereas only one gene encoding the beta subunit has been detected. Ligand binding occurs at the interface of alpha and beta subunits. The beta subunit, which is unable to form homo-oligomeric receptors, is responsible for assembly and channel properties. Moreover, this subunit carries a binding motif for the cytoplasmic protein gephyrin, which is believed to mediate synaptic clustering and anchoring at inhibitory synapses by interacting with the subsynaptic cytoskeleton. Synaptic gephyrin appears to restrict the mobility of glycine receptors diffusing in the plane of the plasma membrane, thereby generating dynamic plasma membrane domains contributing to the plasticity of inhibitory synapses. Glycine receptors are well established as playing important roles in controlling motor functions and sensory signaling in vision and audition and those in the dorsal horn of the spinal cord are now considered to be new targets for pain therapies. Like GABA(A) receptors, glycine receptors have been shown to be depolarizing during development. The functional meaning of the developmental switch from excitatory to inhibitory glycine receptor action remains to be elucidated.

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Low level expression of glycine receptor beta subunit transgene is sufficient for phenotype correction in spastic mice.

Cited by 40 publications

References 46 publications

The Neuronal RNA Binding Protein Nova-1 Recognizes Specific RNA Targets In Vitro and In Vivo

The Neuronal RNA Binding Protein Nova-1 Recognizes Specific RNA Targets In Vitro and In Vivo

Spinal Antiallodynia Action of Glycine Transporter Inhibitors in Neuropathic Pain Models in Mice

Glycinergic transmission

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