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1.
Mol Psychiatry ; 25(11): 3106, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30705428

RESUMO

In the original version of this article, affiliation 3 was given as: "Division of Life Sciences, State Key Laboratory of Molecular Neuroscience, Hong Kong, University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China". This has now been corrected to: "Division of Life Sciences, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China".Additionally in the 'Data availability' section an incorrect accession code was given. The accession code has now been changed from 'PDB A9X (AnkG:GABARAPL)' to 'PDB 6A9X (AnkG:GABARAP)'.These errors have been corrected in both the PDF and HTML versions of the Article.

2.
Mol Psychiatry ; 25(11): 2800-2817, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-30504823

RESUMO

GABAergic circuits are critical for the synchronization and higher order function of brain networks. Defects in this circuitry are linked to neuropsychiatric diseases, including bipolar disorder, schizophrenia, and autism. Work in cultured neurons has shown that ankyrin-G plays a key role in the regulation of GABAergic synapses on the axon initial segment and somatodendritic domain of pyramidal neurons, where it interacts directly with the GABAA receptor-associated protein (GABARAP) to stabilize cell surface GABAA receptors. Here, we generated a knock-in mouse model expressing a mutation that abolishes the ankyrin-G/GABARAP interaction (Ank3 W1989R) to understand how ankyrin-G and GABARAP regulate GABAergic circuitry in vivo. We found that Ank3 W1989R mice exhibit a striking reduction in forebrain GABAergic synapses resulting in pyramidal cell hyperexcitability and disruptions in network synchronization. In addition, we identified changes in pyramidal cell dendritic spines and axon initial segments consistent with compensation for hyperexcitability. Finally, we identified the ANK3 W1989R variant in a family with bipolar disorder, suggesting a potential role of this variant in disease. Our results highlight the importance of ankyrin-G in regulating forebrain circuitry and provide novel insights into how ANK3 loss-of-function variants may contribute to human disease.


Assuntos
Anquirinas/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Vias Neurais , Prosencéfalo/citologia , Prosencéfalo/metabolismo , Adulto , Idoso , Animais , Anquirinas/genética , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Células Cultivadas , Feminino , Neurônios GABAérgicos/metabolismo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Sinapses/metabolismo , Adulto Jovem
3.
Neurosci Lett ; 315(3): 137-40, 2001 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-11716982

RESUMO

Peptide secretion from rat melanotropes is tonically inhibited by a dopaminergic synaptic input that develops after birth and acts through D2 dopamine receptors. In this study, whole-cell Na(+) currents were recorded from melanotropes that were isolated from rat pituitary intermediate lobes at postnatal days 1-20 (P1-P20) and maintained in culture for 5-24 h. Coincident with the development of innervation, melanotropes exhibited a progressive decrease in peak Na(+) current density from P3 to P14. The decrease involved a 50% reduction in maximal Na(+) conductance with no detectable changes in channel gating. Subcutaneous injections of the D2 antagonist sulpiride, applied from P11 to P13, restored melanotrope Na(+) channel activity to pre-innervation levels. Thus, the activation of D2 receptors by the dopaminergic input reduces the functional expression of Na(+) channels in melanotropes.


Assuntos
Animais Recém-Nascidos/metabolismo , Dopamina/fisiologia , Hormônios Estimuladores de Melanócitos/metabolismo , Hipófise/fisiologia , Canais de Sódio/fisiologia , Envelhecimento/fisiologia , Animais , Animais Recém-Nascidos/genética , Células Cultivadas , Condutividade Elétrica , Hipófise/crescimento & desenvolvimento , Ratos , Ratos Wistar
4.
J Physiol ; 523 Pt 1: 45-55, 2000 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-10673544

RESUMO

1. The effects of chronic pharmacological modulation of L-type Ca2+ channel activity on the cell surface expression of Na+ channels were examined in GH3 cells. 2. Prolonged inhibition (4-5 days) of L-channels with nimodipine caused a 50-60 % decrease in the peak amplitude of whole-cell Na+ currents recorded with the patch-clamp technique. On the contrary, prolonged exposure to the L-channel agonist Bay K 8644 induced an approximately 2.5-fold increase in peak Na+ current. In both cases, there were only minor changes in cell capacitance and no significant changes in Na+ channel gating properties. 3. Measurements of the specific binding of radiolabelled saxitoxin to intact cells showed that nimodipine treatment reduced the number of cell surface Na+ channels, whereas treatment with Bay K 8664 produced the opposite effect. The dual regulation of Na+ channel abundance explained the mentioned changes in Na+ current amplitude. 4. Plasma membrane Na+ channels had a half-life of approximately 17 h both in control cells and in cells treated with Bay K 8644, as estimated from the rate of decay of peak Na+ current after inhibition of protein synthesis with cycloheximide. Actinomycin D, an inhibitor of gene transcription, and also cycloheximide, occluded the stimulatory effect of Bay K 8644 on Na+ current density when measured over a 24 h period. 5. These findings indicate that the entry of Ca2+ through L-type channels influences in a positive way the number of functional Na+ channels in GH3 cells, and suggest that Ca2+ influx stimulates either Na+ channel gene expression or the expression of a regulatory protein that promotes translocation of pre-assembled Na+ channels into the plasma membrane.


Assuntos
Canais de Cálcio Tipo L/fisiologia , Hipófise/metabolismo , Canais de Sódio/metabolismo , Éster Metílico do Ácido 3-Piridinacarboxílico, 1,4-Di-Hidro-2,6-Dimetil-5-Nitro-4-(2-(Trifluormetil)fenil)/farmacologia , Animais , Agonistas dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Linhagem Celular , Cicloeximida/farmacologia , Dactinomicina/farmacologia , Eletrofisiologia , Ativação do Canal Iônico/efeitos dos fármacos , Nimodipina/farmacologia , Inibidores da Síntese de Ácido Nucleico/farmacologia , Hipófise/citologia , Inibidores da Síntese de Proteínas/farmacologia , Ratos , Saxitoxina/metabolismo , Canais de Sódio/fisiologia , Transcrição Gênica/efeitos dos fármacos
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