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International Journal of Molecular... Jul 2023Migraine is a debilitating neurological condition affecting millions of people worldwide. Until a few years ago, preventive migraine treatments were based on molecules... (Review)
Review
Migraine is a debilitating neurological condition affecting millions of people worldwide. Until a few years ago, preventive migraine treatments were based on molecules with pleiotropic targets, developed for other indications, and discovered by serendipity to be effective in migraine prevention, although often burdened by tolerability issues leading to low adherence. However, the progresses in unravelling the migraine pathophysiology allowed identifying novel putative targets as calcitonin gene-related peptide (CGRP). Nevertheless, despite the revolution brought by CGRP monoclonal antibodies and gepants, a significant percentage of patients still remains burdened by an unsatisfactory response, suggesting that other pathways may play a critical role, with an extent of involvement varying among different migraine patients. Specifically, neuropeptides of the CGRP family, such as adrenomedullin and amylin; molecules of the secretin family, such as pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP); receptors, such as transient receptor potential (TRP) channels; intracellular downstream determinants, such as potassium channels, but also the opioid system and the purinergic pathway, have been suggested to be involved in migraine pathophysiology. The present review provides an overview of these pathways, highlighting, based on preclinical and clinical evidence, as well as provocative studies, their potential role as future targets for migraine preventive treatment.
Topics: Humans; Animals; Migraine Disorders; Signal Transduction; Vasoactive Intestinal Peptide; Potassium Channels; Analgesics, Opioid
PubMed: 37569648
DOI: 10.3390/ijms241512268 -
Circulation Aug 2023Atrial fibrillation (AF) is by far the most common cardiac arrhythmia. In about 3% of individuals, AF develops as a primary disorder without any identifiable trigger...
BACKGROUND
Atrial fibrillation (AF) is by far the most common cardiac arrhythmia. In about 3% of individuals, AF develops as a primary disorder without any identifiable trigger (idiopathic or historically termed lone AF). In line with the emerging field of autoantibody-related cardiac arrhythmias, the objective of this study was to explore whether autoantibodies targeting cardiac ion channels can underlie unexplained AF.
METHODS
Peptide microarray was used to screen patient samples for autoantibodies. We compared patients with unexplained AF (n=37 pre-existent AF; n=14 incident AF on follow-up) to age- and sex-matched controls (n=37). Electrophysiological properties of the identified autoantibody were then tested in vitro with the patch clamp technique and in vivo with an experimental mouse model of immunization.
RESULTS
A common autoantibody response against K3.4 protein was detected in patients with AF and even before the development of clinically apparent AF. K3.4 protein forms a heterotetramer that underlies the cardiac acetylcholine-activated inwardly rectifying K current, . Functional studies on human induced pluripotent stem cell-derived atrial cardiomyocytes showed that anti-K3.4 IgG purified from patients with AF shortened action potentials and enhanced the constitutive form of , both key mediators of AF. To establish a causal relationship, we developed a mouse model of K3.4 autoimmunity. Electrophysiological study in K3.4-immunized mice showed that K3.4 autoantibodies significantly reduced atrial effective refractory period and predisposed animals to a 2.8-fold increased susceptibility to AF.
CONCLUSIONS
To our knowledge, this is the first report of an autoimmune pathogenesis of AF with direct evidence of K3.4 autoantibody-mediated AF.
Topics: Humans; Animals; Mice; Atrial Fibrillation; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Induced Pluripotent Stem Cells; Heart Atria; Autoantibodies
PubMed: 37401487
DOI: 10.1161/CIRCULATIONAHA.122.062776 -
Cell Sep 2023KCR channelrhodopsins (K-selective light-gated ion channels) have received attention as potential inhibitory optogenetic tools but more broadly pose a fundamental...
KCR channelrhodopsins (K-selective light-gated ion channels) have received attention as potential inhibitory optogenetic tools but more broadly pose a fundamental mystery regarding how their K selectivity is achieved. Here, we present 2.5-2.7 Å cryo-electron microscopy structures of HcKCR1 and HcKCR2 and of a structure-guided mutant with enhanced K selectivity. Structural, electrophysiological, computational, spectroscopic, and biochemical analyses reveal a distinctive mechanism for K selectivity; rather than forming the symmetrical filter of canonical K channels achieving both selectivity and dehydration, instead, three extracellular-vestibule residues within each monomer form a flexible asymmetric selectivity gate, while a distinct dehydration pathway extends intracellularly. Structural comparisons reveal a retinal-binding pocket that induces retinal rotation (accounting for HcKCR1/HcKCR2 spectral differences), and design of corresponding KCR variants with increased K selectivity (KALI-1/KALI-2) provides key advantages for optogenetic inhibition in vitro and in vivo. Thus, discovery of a mechanism for ion-channel K selectivity also provides a framework for next-generation optogenetics.
Topics: Humans; Channelrhodopsins; Cryoelectron Microscopy; Ion Channels; Potassium; Rhinosporidium
PubMed: 37652010
DOI: 10.1016/j.cell.2023.08.009 -
Neurobiology of Disease Sep 2023Lysosomes are acidic intracellular organelles with autophagic functions that are critical for protein degradation and mitochondrial homeostasis, while abnormalities in... (Review)
Review
Lysosomes are acidic intracellular organelles with autophagic functions that are critical for protein degradation and mitochondrial homeostasis, while abnormalities in lysosomal physiological functions are closely associated with neurological disorders. Transmembrane protein 175 (TMEM175), an ion channel in the lysosomal membrane that is essential for maintaining lysosomal acidity, has been proven to coordinate with V-ATPase to modulate the luminal pH of the lysosome to assist the digestion of abnormal proteins and organelles. However, there is considerable controversy about the characteristics of TMEM175. In this review, we introduce the research progress on the structural, modulatory, and functional properties of TMEM175, followed by evidence of its relevance for neurological disorders. Finally, we discuss the potential value of TMEM175 as a therapeutic target in the hope of providing new directions for the treatment of neurodegenerative diseases.
Topics: Humans; Ion Channels; Neurodegenerative Diseases; Lysosomes; Autophagy; Potassium Channels
PubMed: 37524211
DOI: 10.1016/j.nbd.2023.106244 -
Molecular Cell Jul 2023Maintaining a highly acidic lysosomal pH is central to cellular physiology. Here, we use functional proteomics, single-particle cryo-EM, electrophysiology, and in vivo...
Maintaining a highly acidic lysosomal pH is central to cellular physiology. Here, we use functional proteomics, single-particle cryo-EM, electrophysiology, and in vivo imaging to unravel a key biological function of human lysosome-associated membrane proteins (LAMP-1 and LAMP-2) in regulating lysosomal pH homeostasis. Despite being widely used as a lysosomal marker, the physiological functions of the LAMP proteins have long been overlooked. We show that LAMP-1 and LAMP-2 directly interact with and inhibit the activity of the lysosomal cation channel TMEM175, a key player in lysosomal pH homeostasis implicated in Parkinson's disease. This LAMP inhibition mitigates the proton conduction of TMEM175 and facilitates lysosomal acidification to a lower pH environment crucial for optimal hydrolase activity. Disrupting the LAMP-TMEM175 interaction alkalinizes the lysosomal pH and compromises the lysosomal hydrolytic function. In light of the ever-increasing importance of lysosomes to cellular physiology and diseases, our data have widespread implications for lysosomal biology.
Topics: Humans; Hydrogen-Ion Concentration; Lysosomal Membrane Proteins; Lysosomes; Parkinson Disease; Potassium Channels
PubMed: 37390818
DOI: 10.1016/j.molcel.2023.06.004 -
JAMA Neurology Nov 2023Many patients with focal epilepsy experience seizures despite treatment with currently available antiseizure medications (ASMs) and may benefit from novel therapeutics. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Many patients with focal epilepsy experience seizures despite treatment with currently available antiseizure medications (ASMs) and may benefit from novel therapeutics.
OBJECTIVE
To evaluate the efficacy and safety of XEN1101, a novel small-molecule selective Kv7.2/Kv7.3 potassium channel opener, in the treatment of focal-onset seizures (FOSs).
DESIGN, SETTING, AND PARTICIPANTS
This phase 2b, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging adjunctive trial investigated XEN1101 over an 8-week treatment period from January 30, 2019, to September 2, 2021, and included a 6-week safety follow-up. Adults experiencing 4 or more monthly FOSs while receiving stable treatment (1-3 ASMs) were enrolled at 97 sites in North America and Europe.
INTERVENTIONS
Patients were randomized 2:1:1:2 to receive XEN1101, 25, 20, or 10 mg, or placebo with food once daily for 8 weeks. Dosage titration was not used. On completion of the double-blind phase, patients were offered the option of entering an open-label extension (OLE). Patients not participating in the OLE had follow-up safety visits (1 and 6 weeks after the final dose).
MAIN OUTCOMES AND MEASURES
The primary efficacy end point was the median percent change from baseline in monthly FOS frequency. Treatment-emergent adverse events (TEAEs) were recorded and comprehensive laboratory assessments were made. Modified intention-to-treat analysis was conducted.
RESULTS
A total of 325 patients who were randomized and treated were included in the safety analysis; 285 completed the 8-week double-blind phase. In the 325 patients included, mean (SD) age was 40.8 (13.3) years, 168 (51.7%) were female, and 298 (91.7%) identified their race as White. Treatment with XEN1101 was associated with seizure reduction in a robust dose-response manner. The median (IQR) percent reduction from baseline in monthly FOS frequency was 52.8% (P < .001 vs placebo; IQR, -80.4% to -16.9%) for 25 mg, 46.4% (P < .001 vs placebo; IQR, -76.7% to -14.0%) for 20 mg, and 33.2% (P = .04 vs placebo; IQR, -61.8% to 0.0%) for 10 mg, compared with 18.2% (IQR, -37.3% to 7.0%) for placebo. XEN1101 was generally well tolerated and TEAEs were similar to those of commonly prescribed ASMs, and no TEAEs leading to death were reported.
CONCLUSIONS AND RELEVANCE
The efficacy and safety findings of this clinical trial support the further clinical development of XEN1101 for the treatment of FOSs.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03796962.
Topics: Adult; Female; Humans; Male; Anticonvulsants; Double-Blind Method; Drug Therapy, Combination; Epilepsies, Partial; Potassium Channels; Seizures; Treatment Outcome
PubMed: 37812429
DOI: 10.1001/jamaneurol.2023.3542 -
Journal of Translational Medicine Sep 2023Owing to the heterogeneity of Alzheimer's disease (AD), its pathogenic mechanisms are yet to be fully elucidated. Evidence suggests an important role of metabolism in...
BACKGROUND
Owing to the heterogeneity of Alzheimer's disease (AD), its pathogenic mechanisms are yet to be fully elucidated. Evidence suggests an important role of metabolism in the pathophysiology of AD. Herein, we identified the metabolism-related AD subtypes and feature genes.
METHODS
The AD datasets were obtained from the Gene Expression Omnibus database and the metabolism-relevant genes were downloaded from a previously published compilation. Consensus clustering was performed to identify the AD subclasses. The clinical characteristics, correlations with metabolic signatures, and immune infiltration of the AD subclasses were evaluated. Feature genes were screened using weighted correlation network analysis (WGCNA) and processed via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Furthermore, three machine-learning algorithms were used to narrow down the selection of the feature genes. Finally, we identified the diagnostic value and expression of the feature genes using the AD dataset and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis.
RESULTS
Three AD subclasses were identified, namely Metabolism Correlated (MC) A (MCA), MCB, and MCC subclasses. MCA contained signatures associated with high AD progression and may represent a high-risk subclass compared with the other two subclasses. MCA exhibited a high expression of genes related to glycolysis, fructose, and galactose metabolism, whereas genes associated with the citrate cycle and pyruvate metabolism were downregulated and associated with high immune infiltration. Conversely, MCB was associated with citrate cycle genes and exhibited elevated expression of immune checkpoint genes. Using WGCNA, 101 metabolic genes were identified to exhibit the strongest association with poor AD progression. Finally, the application of machine-learning algorithms enabled us to successfully identify eight feature genes, which were employed to develop a nomogram model that could bring distinct clinical benefits for patients with AD. As indicated by the AD datasets and qRT-PCR analysis, these genes were intimately associated with AD progression.
CONCLUSION
Metabolic dysfunction is associated with AD. Hypothetical molecular subclasses of AD based on metabolic genes may provide new insights for developing individualized therapy for AD. The feature genes highly correlated with AD progression included GFAP, CYB5R3, DARS, KIAA0513, EZR, KCNC1, COLEC12, and TST.
Topics: Humans; Alzheimer Disease; Algorithms; Citrates; Citric Acid; Cluster Analysis; Shaw Potassium Channels; Nerve Tissue Proteins
PubMed: 37715200
DOI: 10.1186/s12967-023-04324-y