Methylation determines the extracellular calcium sensitivity of the leak channel NALCN in hippocampal dentate granule cells

Experimental & Molecular Medicine, Journal Year: 2019, Volume and Issue: 51(10), P. 1 - 14

Published: Oct. 1, 2019

Abstract The sodium leak channel NALCN is a key player in establishing the resting membrane potential (RMP) neurons and transduces changes extracellular Ca 2+ concentration ([Ca ] e ) into increased neuronal excitability as downstream effector of calcium-sensing receptor (CaSR). Gain-of-function mutations human gene cause encephalopathy severe intellectual disability. Thus, understanding regulatory mechanisms important for both basic translational research. This study reveals novel mechanism regulation by arginine methylation. Hippocampal dentate granule cells protein methyltransferase 7 (PRMT7)-deficient mice display depolarization RMP, decreased threshold currents, compared to wild-type neurons. Electrophysiological studies combined with molecular analysis indicate that enhanced activities contribute hyperexcitability PRMT7−/− PRMT7 depletion HEK293T increases activity shifting dose-response curve inhibition [Ca without affecting levels. In vitro methylation show methylates highly conserved Arg1653 located carboxy-terminal region implicated CaSR-mediated regulation. A kinase-specific phosphorylation site prediction program shows adjacent Ser1652 site. Consistently, our data from site-specific mutants PKC inhibitors suggest might modulate mediated CaSR/PKC-delta, leading -mediated suppression. Collectively, these deficiency decreases at Arg1653, which, turn, CaSR/PKC-mediated phosphorylation, lifting inhibition, thereby enhancing excitability. PRMT7-mediated provides target development therapeutic tools neurological diseases.

Language: Английский

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Kv7.4 Channel Contribute to Projection-Specific Auto-Inhibition of Dopamine Neurons in the Ventral Tegmental Area

Frontiers in Cellular Neuroscience, Journal Year: 2019, Volume and Issue: 13

Published: Dec. 18, 2019

Dopaminergic neurons in ventral tegmental area (VTA) encode behavioural patterns important reward and drug addiction as well emotional disorders. These functions of dopamine are directly related to the release targeted regions brain which are, thus, controlled by excitability neurons. One mechanism for modulation neuronal is mediated auto type 2 (D2) receptors, through activation a Kir3/GIRK K+ channel inhibits firing In this study, we provide evidence that Kv7.4, addition Kir3.2 channels, contributes DA-mediated auto-inhibition DA activity projecting NAc BLA. Furthermore demonstrate D2 receptors enhance Kv7.4 currents Gi/o protein redox-dependent cellular pathway. Finally, show blunted social defeat mice model depression, phenomenon may contribute altered VTA depressed animals. results new perspective understanding molecular potential strategies against mental disorders involving neurons, such major depression addictions.

Language: Английский

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Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: July 3, 2020

Abstract The sodium-leak channel NALCN forms a subthreshold sodium conductance that controls the resting membrane potentials of neurons. auxiliary subunits and their functions in mammals are largely unknown. In this study, we demonstrate two large proteins UNC80 UNC79 complex. knockout mice neonatal lethal. C-terminus contains domain interacts with overcomes soma-retention signal to achieve dendritic localization. lacking domain, as found human patients, still supports whole-cell currents but lacks Our results establish subunit composition complex, uncover inter-subunit interaction domains, reveal functional significance regulation potential by provide evidence supporting genetic variations individuals intellectual disability causes for phenotype observed patients.

Language: Английский

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Presynaptic Gαo (GOA-1) signals to depress command neuron excitability and allow stretch-dependent modulation of egg laying in Caenorhabditis elegans

Genetics, Journal Year: 2021, Volume and Issue: 218(4)

Published: May 25, 2021

Abstract Egg laying in the nematode worm Caenorhabditis elegans is a two-state behavior modulated by internal and external sensory input. We have previously shown that homeostatic feedback of embryo accumulation uterus regulates bursting activity serotonergic HSN command neurons sustains egg-laying active state. How egg release signals to terminate state less understood. find Gαo, conserved Pertussis Toxin-sensitive G protein, within inhibit circuit prevent entry into Gαo signaling hyperpolarizes HSN, reducing Ca2+ input onto postsynaptic vulval muscles. Loss inhibitory uncouples presynaptic from postsynaptic, stretch-dependent homeostat, causing precocious when only few eggs are present uterus. Feedback opening activates uv1 neuroendocrine cells which NLP-7 neuropeptides signal through Gαo-independent mechanisms HSNs Gαo-dependent other than HSNs. Thus, neuropeptide maintain bi-stable electrical excitability dynamically controls response both drive output.

Language: Английский

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Maternal smoking during pregnancy and risks to depression and anxiety in offspring: An observational study and genome-wide gene-environment interaction analysis in UK biobank cohort

Journal of Psychiatric Research, Journal Year: 2021, Volume and Issue: 140, P. 149 - 158

Published: May 27, 2021

Language: Английский

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