Role of sodium leak channel (NALCN) in sensation and pain: an overview

Zhang, Donghang; Wei, Yiyong

doi:10.3389/fphar.2023.1349438

Cited by 3 publications

(1 citation statement)

References 41 publications

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“…According to a bioinformatics study, unc-80 has been suggested to be a hub gene for pancreatic cancer [127]. NALCN plays an important role in pacemaker activity [128], sensation, and pain [129]. We speculate that the presence of anti-spike antibodies that cross-react with unc-80 may partly explain the diverse range of symptoms in patients with COVID-19 and long COVID.…”

Section: The Human Unc-80 Protein Is a Potential Target Of An Autoant...mentioning

confidence: 93%

In Silico and In Vitro Evaluation of the Molecular Mimicry of the SARS-CoV-2 Spike Protein by Common Short Constituent Sequences (cSCSs) in the Human Proteome: Toward Safer Epitope Design for Vaccine Development

Mizuno,

Nakasone,

Nakamura

et al. 2024

Vaccines

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Spike protein sequences in SARS-CoV-2 have been employed for vaccine epitopes, but many short constituent sequences (SCSs) in the spike protein are present in the human proteome, suggesting that some anti-spike antibodies induced by infection or vaccination may be autoantibodies against human proteins. To evaluate this possibility of “molecular mimicry” in silico and in vitro, we exhaustively identified common SCSs (cSCSs) found both in spike and human proteins bioinformatically. The commonality of SCSs between the two systems seemed to be coincidental, and only some cSCSs were likely to be relevant to potential self-epitopes based on three-dimensional information. Among three antibodies raised against cSCS-containing spike peptides, only the antibody against EPLDVL showed high affinity for the spike protein and reacted with an EPLDVL-containing peptide from the human unc-80 homolog protein. Western blot analysis revealed that this antibody also reacted with several human proteins expressed mainly in the small intestine, ovary, and stomach. Taken together, these results showed that most cSCSs are likely incapable of inducing autoantibodies but that at least EPLDVL functions as a self-epitope, suggesting a serious possibility of infection-induced or vaccine-induced autoantibodies in humans. High-risk cSCSs, including EPLDVL, should be excluded from vaccine epitopes to prevent potential autoimmune disorders.

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Section: The Human Unc-80 Protein Is a Potential Target Of An Autoant...mentioning

confidence: 93%

In Silico and In Vitro Evaluation of the Molecular Mimicry of the SARS-CoV-2 Spike Protein by Common Short Constituent Sequences (cSCSs) in the Human Proteome: Toward Safer Epitope Design for Vaccine Development

Mizuno,

Nakasone,

Nakamura

et al. 2024

Vaccines

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Gabapentin’s Effect on Human Dorsal Root Ganglia: Donor-Specific Electrophysiological and Transcriptomic Profiles

Demeter,

Zurek,

Koch

et al. 2024

Preprint

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Neuropathic pain affects approximately 10% of the adult population and is commonly treated with gabapentin (GBP), a repurposed anticonvulsant drug. Despite its widespread clinical use, GBPs efficacy varies significantly among patients, highlighting the need to better understand its functional and molecular impacts on human pain-sensing neurons. In this study, we characterized the electrophysiological and transcriptomic effects of GBP on primary sensory neurons derived from the dorsal root ganglia (DRG) of ethically consented human donors. Using patch-clamp electrophysiology, we demonstrated that GBP treatment reduced neuronal excitability, with more pronounced effects in multi-firing vs. single-firing neuronal subtypes. Notably, significant donor-specific variability was observed in electrophysiological responsiveness to GBP treatment in vitro. RNA sequencing of DRG tissue from the GBP-responsive donor revealed differences in the transcriptome-wide expression of genes associated with ion transport, synaptic transmission, inflammation, and immune response relative to non-responsive donors. Cross-transcriptomic analyses further showed that GBP treatment counteracted these altered processes, rescuing aberrant gene expression at the pathway level and for several key genes. This study provides a comprehensive electrophysiological and transcriptomic profile of the effects of GBP on human DRG neurons. These findings enhance our understanding of GBPs mechanistic actions on peripheral sensory neurons and could help optimize its clinical use for neuropathic pain management.

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Widening the infantile hypotonia with psychomotor retardation and characteristic Facies-1 Syndrome’s clinical and molecular spectrum through NALCN in-silico structural analysis

Vecchio,

Macchiaiolo,

Gonfiantini

et al. 2024

Front. Genet.

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IntroductionInfantile hypotonia with psychomotor retardation and characteristic facies-1 (IHPRF1, MIM#615419) is a rare, birth onset, autosomal recessive disorder caused by homozygous or compound heterozygous truncating variants in NALCN gene (MIM#611549) resulting in a loss-of-function effect.MethodsWe enrolled a new IHPRF1 patients’ cohort in the framework of an international multicentric collaboration study. Using specialized in silico pathogenicity predictors and ad hoc structural analyses, we assessed the mechanistic consequences of the deleterious variants retrieved on NALCN structure and function.ResultsTo date 38 different NALCN variants have been retrieved from 33 different families, 26 from unrelated and 22 from related patients. We report on five new IHPRF1 patients from four different families, harboring four newly identified and one previously retrieved variant that exhibited a markedly significant functional impact, thereby compromising the functionality of the protein complex.DiscussionBy widening the functional spectrum of biallelic variants affecting the NALCN gene, this article broadens the IHPRF1 syndrome’s genotype-phenotype correlation and gives new insight into its pathogenic mechanism, diagnosis, and clinical management.

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Role of sodium leak channel (NALCN) in sensation and pain: an overview

Cited by 3 publications

References 41 publications

In Silico and In Vitro Evaluation of the Molecular Mimicry of the SARS-CoV-2 Spike Protein by Common Short Constituent Sequences (cSCSs) in the Human Proteome: Toward Safer Epitope Design for Vaccine Development

In Silico and In Vitro Evaluation of the Molecular Mimicry of the SARS-CoV-2 Spike Protein by Common Short Constituent Sequences (cSCSs) in the Human Proteome: Toward Safer Epitope Design for Vaccine Development

Gabapentin’s Effect on Human Dorsal Root Ganglia: Donor-Specific Electrophysiological and Transcriptomic Profiles

Widening the infantile hypotonia with psychomotor retardation and characteristic Facies-1 Syndrome’s clinical and molecular spectrum through NALCN in-silico structural analysis

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