Ribosome profiling reveals that post-transcriptional control of Nalf1 by heterogeneous nuclear ribonucleoprotein L is required for paclitaxel-induced neuropathic pain

Pain, Journal Year: 2025, Volume and Issue: unknown

Published: April 2, 2025

Abstract Sensory neurons are integral to the genesis and maintenance of neuropathic pain. The molecular mechanisms that mediate long-lived changes in their excitability unclear. Here, we leverage functional genomics approaches survey RNA abundance translation dorsal root ganglion from a mouse model paclitaxel-induced We focus specifically on females as paclitaxel is first-line therapy for breast cancer. sequencing data indicate substantially more occur at level (n = 404) than transcription decay 109). discovered core subunit sodium leak channel (NALCN) channel, auxiliary factor 1 (NALF1), preferentially translated response paclitaxel. This effect mediated by RNA-binding protein heterogeneous nuclear ribonucleoprotein L (HNRNP L). Heterogeneous binds 14 base CA-rich element (CARE) Nalf1 3′ untranslated region (3′UTR). Genetic elimination either HNRNP L, CARE motif, or pore-forming nonselective NALCN diminishes pain amplification vivo. Collectively, these results illustrate an situated 3′UTR required female mice.

Language: Английский

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Loss of Atoh1 from neurons regulating hypoxic and hypercapnic chemoresponses causes neonatal respiratory failure in mice

eLife, Journal Year: 2018, Volume and Issue: 7

Published: July 4, 2018

Atoh1-null mice die at birth from respiratory failure, but the precise cause has remained elusive. Loss of Atoh1 various components circuitry (e.g. retrotrapezoid nucleus (RTN)) so far produced most 50% neonatal lethality. To identify other Atoh1-lineage neurons that contribute to postnatal survival, we examined parabrachial complex derived rostral rhombic lip (rRL) and found they are activated during chemochallenges. Atoh1-deletion rRL does not affect causes apneas depression hypoxia, likely due loss projections preBötzinger Complex RTN. thus promotes development neural circuits governing hypoxic hypercapnic (RTN) chemoresponses, combined these regions fully penetrant This work underscores importance modulating rhythms in response chemosensory information early life.

Language: Английский

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NALCN channels enhance the intrinsic excitability of spinal projection neurons

Pain, Journal Year: 2018, Volume and Issue: 159(9), P. 1719 - 1730

Published: April 26, 2018

Abstract Spinal projection neurons convey nociceptive signals to multiple brain regions including the parabrachial (PB) nucleus, which contributes emotional valence of pain perception. Despite clear importance processing, our understanding factors that shape their intrinsic membrane excitability remains limited. Here, we investigate a potential role for Na + leak channel NALCN in regulating activity spino-PB developing rodent. Pharmacological reduction current (I ), or genetic deletion channels, significantly reduced lamina I neurons. In addition, substance P (SP) activated ascending through downstream Src kinase signaling, and knockout prevented SP-evoked action discharge this neuronal population. These results identify, first time, as strong regulator within central circuits also elucidate an additional ionic mechanism by SP can modulate spinal processing. Collectively, these findings indicate level conductance tightly governs transmission thereby potentially influences

Language: Английский

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Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties

Scientific Reports, Journal Year: 2019, Volume and Issue: 9(1)

Published: Aug. 13, 2019

Abstract The excitability of neurons is tightly dependent on their ion channel repertoire. Among these channels, the leak sodium NALCN plays a crucial role in maintenance resting membrane potential. Importantly, mutations lead to complex neurodevelopmental syndromes, including infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) congenital contractures limbs face, developmental delay (CLIFAHDD), which are recessively dominantly inherited, respectively. Unfortunately, biophysical properties still largely unknown date, as well functional consequences both IHPRF CLIFAHDD current. Here we have set-up heterologous expression neuronal cell line NG108-15 investigate electrophysiological carrying representative mutations. Several original wild-type (wt) current were retrieved: mainly carried by external Na + , blocked Gd 3+ insensitive TTX potentiated low Ca 2+ concentration. However, found that this displays time-dependent inactivation −80/−40 mV range potential, non linear current-voltage relationship indicative voltage sensitivity. no detectable was recorded missense mutation p.Trp1287Leu (W1287L), while mutants, p.Leu509Ser (L509S) p.Tyr578Ser (Y578S), showed higher densities slower inactivation, compared wt This study reveals can be achieved mutants. From our results, conclude loss- gain-of-function variants,

Language: Английский

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Aprepitant as a combinant with Dexamethasone reduces the inflammation via Neurokinin 1 Receptor Antagonism in severe to critical Covid-19 patients and potentiates respiratory recovery: A novel therapeutic approach

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2020, Volume and Issue: unknown

Published: Aug. 4, 2020

Abstract Background Corona virus infection is a respiratory infection, compromising the normal breathing in critical patients by damaging lungs. Researches are ongoing to find an efficient treatment strategy for this disease either inactivating or boosting immune system of patient managing cytokine storm. Aim To evaluate clinical outcomes Substance P receptor Neurokinin 1 antagonist Covid-19 against usual treatments as controls. Patients and Methods It randomized trial, open label, having two arms, one receiving management care while other Neurokinin-1 Receptor antagonist, Aprepitant, addition. Dexamethasone, corticosteroid also administered orally both groups. PCR positive, hospitalized with more than 18 years age, genders, moderate phase were included. randomly allocated 10 group A 8 B. Lab investigations performed groups before after intervention. We report preliminary results comparison Aprepitant 80 mg given once daily 3-5 days vs routine management. The primary outcome was total hospital duration disease. Results Mean age 47.63 ±12.07years 60.90± 9.75 There 3/8 males 8/10 2 5 Biochemical hematological parameters didn’t show much difference except C-reactive protein reduction intervention group, indicative reduced inflammation. Oxygen saturation improved but should be enrolled get statistically significant data. One discharged from each within expired each. Conclusions pilot study findings give strong clue therapeutic potential Aprepitant. who received combination therapy Dexamethasone recovered earlier showed outcomes, laboratory which inflammatory marker. suggest here on larger sample size deeper insight its efficacy. may effective severe difficulties.

Language: Английский

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Transformation of Our Understanding of Breathing Control by Molecular Tools

Annual Review of Physiology, Journal Year: 2022, Volume and Issue: 85(1), P. 93 - 113

Published: Nov. 2, 2022

The rhythmicity of breath is vital for normal physiology. Even so, breathing enriched with multifunctionality. External signals constantly change breathing, stopping it when under water or deepening during exertion. Internal cues utilize to express emotions such as sighs frustration and yawns boredom. Breathing harmonizes other actions that use our mouth throat, including speech, chewing, swallowing. In addition, perception intensity can dictate how we feel, the slow calming meditation anxiety-inducing hyperventilation. Heartbeat originates from a peripheral pacemaker in heart, but automation arises neural clusters within brainstem, enabling interaction brain areas thus Here, document recent transformation cellular molecular tools has contributed appreciation diversity neuronal types control circuit they confer multifunctionality breathing.

Language: Английский

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Dopamine negatively modulates the NCA ion channels in C. elegans

PLoS Genetics, Journal Year: 2017, Volume and Issue: 13(10), P. e1007032 - e1007032

Published: Oct. 2, 2017

The NALCN/NCA ion channel is a cation related to voltage-gated sodium and calcium channels. NALCN has been reported be leak with conserved role in establishing neuronal resting membrane potential, but its precise cellular regulation are unclear. Caenorhabditis elegans orthologs of NALCN, NCA-1 NCA-2, act premotor interneurons regulate motor circuit activity that sustains locomotion. Recently we found NCA-2 activated by signal transduction pathway acting downstream the heterotrimeric G protein Gq small GTPase Rho. Through forward genetic screen, here identify GPCR kinase GRK-2 as new player affecting signaling through Gq-Rho-NCA pathway. Using structure-function analysis, find phosphorylation association domains required for function. Genetic epistasis experiments suggest acts on D2-like dopamine receptor DOP-3 inhibit Go positively modulate activity. cell-specific rescuing experiments, NCA Finally, demonstrate dopamine, DOP-3, negatively regulates Thus, this study identifies which modulates

Language: Английский

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Motor neuron degeneration correlates with respiratory dysfunction in SCA1

Disease Models & Mechanisms, Journal Year: 2018, Volume and Issue: 11(2)

Published: Feb. 1, 2018

Spinocerebellar ataxia type 1 (SCA1) is characterized by adult-onset cerebellar degeneration with attendant loss of motor coordination. Bulbar function eventually impaired and patients typically die from an inability to clear the airway. We investigated whether neuron at root bulbar dysfunction studying SCA1 knock-in (Atxn1154Q/+ ) mice. Spinal cord brainstem neurons were assessed in Atxn1154Q/+ mice 1, 3 6 months age. Specifically, we breathing physiology, diaphragm histology electromyography, immunohistochemistry. show progressive neuromuscular respiratory abnormalities, neurogenic changes diaphragm, spinal brainstem. Motor accompanied reactive astrocytosis accumulation Atxn1 aggregates nuclei. This observation correlates previous findings patient tissue. develop because degeneration. These confirm line as a model face construct validity for this understudied disease feature. Furthermore, suitable pathogenic mechanism driving possibly other degenerative diseases. From clinical standpoint, data indicate that pulmonary testing employment non-invasive ventilator support could be beneficial patients. The physiological tests used study might serve valuable biomarkers future therapeutic interventions trials.This article has associated First Person interview first author paper.

Language: Английский

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Neuromodulation of central pattern generators and its role in the functional recovery of central pattern generator activity

Journal of Neurophysiology, Journal Year: 2019, Volume and Issue: 122(1), P. 300 - 315

Published: May 8, 2019

Neuromodulators play an important role in how the nervous system organizes activity that results behavior. Disruption of normal patterns neuromodulatory release or production is known to be related onset severe pathologies such as Parkinson’s disease, Rett syndrome, Alzheimer’s and affective disorders. Some these involve neuronal structures are called central pattern generators (CPGs), which involved rhythmic activities throughout system. Here I discuss interplay between CPGs activity, with particular emphasis on potential neuromodulators recovery disrupted activity. refer invertebrate vertebrate model systems some lessons we have learned from research propose a few avenues for future research. make one suggestion may guide field: restrict parameter landscape CPG components operate, removal enable perturbed finding new set values can allow it regain function.

Language: Английский

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Volatile Anesthetics Activate a Leak Sodium Conductance in Retrotrapezoid Nucleus Neurons to Maintain Breathing during Anesthesia in Mice

Anesthesiology, Journal Year: 2020, Volume and Issue: 133(4), P. 824 - 838

Published: Aug. 4, 2020

Background Volatile anesthetics moderately depress respiratory function at clinically relevant concentrations. Phox2b-expressing chemosensitive neurons in the retrotrapezoid nucleus, a control center, are activated by isoflurane, but underlying mechanisms remain unclear. The hypothesis of this study was that sodium leak channel contributes to volatile anesthetics-induced modulation nucleus and output. Methods contribution channels isoflurane-, sevoflurane-, propofol-evoked activity output were evaluated wild-type genetically modified mice lacking (both sexes). Patch-clamp recordings performed acute brain slices. Whole-body plethysmography used measure activity. Results Isoflurane 0.42 0.50 mM (~1.5 minimum alveolar concentration) increased channel–mediated holding currents conductance from −75.0 ± 12.9 −130.1 34.9 pA (mean SD, P = 0.002, n 6) 1.8 0.5 3.6 1.0 nS (P 0.001, 6), respectively. At these concentrations, isoflurane 1.1 0.2 2.8 Hz < 5), which eliminated bath application gadolinium or genetic silencing channel. Genetic resulted diminished ventilatory response carbon dioxide under conditions during anesthesia. Sevoflurane produced an effect comparable whereas propofol did not activate conductance. Conclusions sevoflurane increase neuronal excitability partly enhancing Sodium expression is required for anesthesia sevoflurane, thus identifying as requisite determinant anesthetics. Editor’s Perspective What We Already Know about This Topic Article Tells Us That Is New

Language: Английский

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