Biology subjects

Wang, K.

Publications and source records attributed to Wang, K..

At least 199 records · Page 11Linked to original sources

bioRxiv2024

Single cell genome and epigenome co-profiling reveals hardwiring and plasticity in breast cancer

Understanding the impact of genetic alterations on epigenomic phenotypes during breast cancer progression is challenging with unimodal measurements. Here, we report wellDA-seq, the first high-genomic resolution, high-throughput method that can simultaneously measure the whole genome and chromatin accessibility profiles of thousands of single cells. Using wellDA-seq, we profiled 22,123 single cells from 2 normal and 9 tumors breast tissues. By directly mapping the epigenomic phenotypes to genetic lineages across cancer subclones, we found evidence of both genetic hardwiring and epigenetic plasticity. In 6 estrogen-receptor positive breast cancers, we directly identified the ancestral cancer cells, and found that their epithelial cell-of-origin was Luminal Hormone Responsive cells. We also identified cell types with copy number aberrations (CNA) in normal breast tissues and discovered non-epithelial cell types in the microenvironment with CNAs in breast cancers. These data provide insights into the complex relationship between genetic alterations and epigenomic phenotypes during breast tumor evolution.

genomics↗

bioRxiv2024

Identification of leptolin as a novel anti-obesity adipokine

Adipokines are key factors in regulating energy homeostasis. We identified a novel adipokine; we named it Leptolin. In humans, leptolin levels in white adipose tissue were positively corrected with exercise, and negatively associated with body mass index. Leptolin levels were positively correlated with lipolysis-promoting gene expression. Elevated leptolin in plasma of athletes, whereas lowered leptolin in plasma of obese individuals were observed. Leptolin gene-knockout mice exhibited increased adiposity and body weight, and decreased energy expenditure. Leptolin gene-overexpression mice showed obesity-resistant phenotypes. Treatment with leptolin promoted fat mobilization and energy expenditure, and reduced body weight, without affecting food-intake and motor activity. Together, leptolin, a novel adipokine with a capacity to improve metabolic status, may serve as a new therapeutic agent for obesity and metabolic disorders.

physiology↗

bioRxiv2024

The small MAF transcription factor MAFG co-opts MITF to promote melanoma progression

Transcription factor deregulation potently drives melanoma progression by dynamically and reversibly controlling gene expression programs. We previously identified the small MAF family transcription factor MAFG as a putative driver of melanoma progression, prompting an in-depth evaluation of its role in melanoma. MAFG expression increases with human melanoma stages and ectopic MAFG expression enhances the malignant behavior of human melanoma cells in vitro, xenograft models, and genetic mouse models of spontaneous melanoma. Moreover, MAFG induces a melanoma phenotype switch from a melanocytic state to a more dedifferentiated state. Mechanistically, MAFG interacts with the lineage transcription factor MITF which is required for the pro-tumorigenic effects of MAFG. MAFG and MITF co-occupy numerous genomic sites and MAFG overexpression influences the expression of genes harboring binding sites for the MAFG[~]MITF complex. These results establish MAFG as a potent driver of melanomagenesis through dimerization with MITF and uncover an unappreciated mechanism of MITF regulation. Significance statementMITF is critically involved in melanoma progression and phenotype switching. We discovered that MAFG interacts with MITF to influence expression of MITF target genes and facilitate a shift toward a dedifferentiated melanoma cell state. This study demonstrates that MAFG promotes melanomagenesis by influencing MITF activity, an unappreciated mechanism of MITF regulation.

cancer biology↗

bioRxiv2024

Cis-regulatory elements driving motor neuron-restricted viral payload expression within the mammalian spinal cord

Spinal motor neuron (MN) dysfunction is the cause of a number of clinically significant movement disorders. Despite the recent approval of gene therapeutics targeting these MN-related disorders, there are no viral delivery mechanisms that achieve MN-restricted transgene expression. In this study, chromatin accessibility profiling of genetically defined mouse MNs was used to identify candidate cis-regulatory elements (CREs) capable of driving MN-selective gene expression. Subsequent testing of these candidates identified two CREs that confer MN-selective gene expression in the spinal cord as well as reduced off-target expression in dorsal root ganglia. Within one of these candidate elements, we identified a compact core transcription factor (TF)-binding region that drives MN-selective gene expression. Finally, we demonstrate that selective spinal cord expression of this mouse CRE is preserved in non-human primates. These findings suggest that the generation of cell-type-selective viral reagents, in which cell-type-selective CREs drive restricted gene expression, will be valuable research tools in mice and other mammalian species, with potentially significant therapeutic value in humans. SIGNIFICANCE STATEMENTMotor neurons transduce the motor outputs of nervous system activity to muscle and are the vulnerable neurons in a number of clinically significant degenerative conditions, including spinal muscular atrophy and amyotrophic lateral sclerosis. A recent strategy for treating motor neuron degenerative diseases has been to use viruses to introduce genes into motor neurons to inhibit the degenerative process. However, we still lack viral reagents that promote gene expression in motor neurons without potentially toxic off-target expression in other cell types. Our study identifies cis-regulatory elements capable of conferring motor neuron-selective transgene expression in a viral context. These findings have important implications for future gene therapeutics for motor neuron-related disorders.

neuroscience↗

bioRxiv2024

Memorize multiple phase pattern attractors in nonlinear coupled oscillators dynamic via heterogeneous connectivity strength

Whole brain neural oscillation activities exhibit multiple wave patterns and seem to be supported by the common circuit network structure. We proposed a Hebbian-like Kuramoto model based entirely on heterogeneous connectivity strength rather than phase delay, which encodes the multiple phase patterns as attractors. We systematically investigated how the model dynamic landscape influenced by attractors and their corresponding eigenvalues, as well as how to control the stability of equilibrium points and the occurrence of high dimension bifurcations. This framework enables us to reproduce the dominant wave activity components in human brain functional MRI signal, and provides a canonical model for the multi body physical system spatio-temporal pattern attractor dynamics.

neuroscience↗

bioRxiv2024

B cells targeting parasites capture spatially linked antigens to secure T cell help

Our understanding of T-cell-dependent humoral responses has been largely shaped by studies involving model antigens such as recombinant proteins and viruses 1,2. In these contexts, B cells internalize the entire antigen or pathogen, and present a range of antigens to helper CD4+ T cells to initiate the humoral response. However, this model does not account for large pathogens (such as parasites) that are too large to be taken up by individual B cells, and the mechanisms by which B cells acquire and present antigens from large complex pathogens to T cells remain poorly understood. Here we used Plasmodium, the causative parasite of malaria, as a model to investigate the requirements for T cell help for B cells targeting the Plasmodium surface circumsporozoite protein (CSP). Upon Plasmodium sporozoite (SPZ) immunization, CSP-specific B cells can form a synapse-like structure with SPZs and take up CSP and non-CSP surface antigens. As a result, CSP-specific B cells can receive help from CD4+ T cells specific to antigens that are located on the surface but not cytosol of the Plasmodium SPZ. Therefore, B cells can obtain help, not only from T cells with the same protein specificity, but also from T cells specific for spatially linked antigens. This flexibility in T cell help may enhance the initiation and maintenance of humoral immune responses to complex pathogens.

immunology↗

bioRxiv2024

LongReadSum: A fast and flexible quality control and signal summarization tool for long-read sequencing data

While several well-established quality control (QC) tools are available for short reads sequencing data, there is a general paucity of computational tools that provide long read metrics in a fast and comprehensive manner across all major sequencing platforms (such as PacBio, Oxford Nanopore, Illumina Complete Long Read) and data formats (such as ONT POD5, FAST5, basecall summary files and PacBio unaligned BAM). Additionally, none of the current tools provide support for summarizing Oxford Nanopore basecall signal or comprehensive base modification (methylation) information from genomic data. Furthermore, nowadays a single PromethION flowcell on the Oxford Nanopore platform can generate terabytes of signal data, which cannot be handled by existing tools designed for small-scale flowcells. To address these challenges, here we present LongReadSum, a multi-threaded C++ tool which provides fast and comprehensive QC reports on all major aspects of sequencing data (such as read, base, base quality, alignment, and base modification metrics) and produce basecalling signal intensity information from the Oxford Nanopore platform. We demonstrate use cases to analyze cDNA sequencing, direct mRNA sequencing, reduced representation methylation sequencing (RRMS) through adaptive sequencing, as well as whole genome sequencing (WGS) data using diverse long-read platforms.

bioinformatics↗

bioRxiv2024

Uncovering Individualized Cerebellar Atrophy Pattern and Behavioral Links in Children with Brainstem Tumor

Background and PurposeBrainstem tumors are rare but cause enduring behavioral issues, challenging patients and surgeons. Research on cerebellar changes in these patients limited, despite symptoms similar to cerebellar injuries. This study aims to investigate cerebellar damage pattern resulting from brainstem tumors and its association with behavioral disorders. MethodsIn this study, a U-Net-based segmentation algorithm was used to divide the cerebellum into 26 lobules, which were then used to build a normative model for assessing individual structural deviations. Furthermore, a behavior prediction model was developed using the total outlier count (tOC) index and brain volume as predictive features. ResultsMost patients were found to have negative deviations in cerebellar regions, particularly in anterior lobules like Left V. Higher tOC was significantly associated with severe social problems (r = 0.31, p = 0.001) and withdrawal behavior (r = 0.28, p = 0.001). Smaller size of cerebellar regions strongly correlated with more pronounced social problems (r = 0.27, p = 0.007) and withdrawal behavior (r = 0.25, p = 0.015). Notably, lobules Right X, V, IV, VIIB, Left IX, VIII, and X influenced social problems, while Left V, Right IV, Vermis VI, and VIII impacted withdrawal behavior. ConclusionsOur study revealed cerebellar damage patterns in patients with brainstem tumors, emphasizing the role of both anterior and posterior cerebellar lobes in social problems and withdrawal behavior. This research sheds light on the brain mechanisms underlying complex behavioral disorders in brainstem tumor patients.

neuroscience↗

bioRxiv2024

Normative Growth Modeling of Cortical Thickness Identify Neuroanatomical Variability and Distinct Subtypes in Brainstem Tumor Patients

BackgroundBrainstem tumors can cause structural brain changes, but the resulting heterogeneity within wholebrain structure is not well-studied. This study examines cortical thickness to identify patterns of structural alterations and explore underlying biological subtypes and their associations with clinical factors. Materials and MethodsThis study involved 124 pediatric brainstem tumor patients, aged 4-18 years. Cortical thickness was measured using CAT12 segmentation of 3D T1-weighted structural MRI. A normative model was established using data from 849 healthy children. Deviations in cortical thickness were estimated, and patients were classified into two subtypes using spectral clustering. Clinical statistical analyses were conducted with SPSS 26.0. ResultsThe normative model revealed significant heterogeneity in cortical thickness deviations, which correlated with tumor size and growth patterns. Focal tumors primarily caused negative deviations (t = 3.14, p = 0.02). There was a significant positive correlation between extreme positive deviations and tumor volume (r = 0.214, p = 0.010), and between extreme negative deviations and progression-free survival (r = 0.39, p = 0.008). Two subtypes were identified: Subtype 1, consisting of diffuse tumors with extreme positive deviations, and Subtype 2, consisting of focal tumors with extreme negative deviations. Subtype and tumor growth pattern significantly influenced duration (p < 0.01). The Kaplan-Meier survival curves for Subtype 1 and Subtype 2 demonstrated a significant difference in survival probabilities over time (p = 0.03). ConclusionOverall, this study identifies two major patterns of cortical thickness changes in brainstem tumor patients, enhancing our understanding of their relationship with cortical morphology. The findings suggest that cortical thickness alterations could serve as valuable biomarkers for predicting progression-free survival, which is crucial for clinical assessment and personalized treatment strategies. This research provides new insights into the physiological mechanisms by which brainstem tumors affect brain structure, supporting more precise clinical interventions and efficacy monitoring in the future.

neuroscience↗

bioRxiv2024

Label-free multiphoton imaging reveals volumetric shifts across development in sensory-related brain regions of a miniature transparent vertebrate

Animals integrate information from different sensory modalities as they mature and perform increasingly complex behaviors. This may parallel differential investment in specific brain regions depending on the demands of changing sensory inputs. To investigate developmental changes in the volume of canonical sensory integration brain regions, we used third harmonic generation imaging for morphometric analysis of forebrain and midbrain regions from 5 to 90 days post fertilization (dpf) in Danionella dracula, a transparent, miniature teleost fish whose brain is optically accessible throughout its lifespan. Relative to whole brain volume, increased volume or investment in telencephalon, a higher order sensory integration center, and torus longitudinalis (TL), a midbrain visuomotor integration center, is relatively consistent from 5 to 30 dpf, until it increases at 60 dpf, followed by another increase at 90 dpf, as animals reach adulthood. In contrast, investment in midbrain optic tectum (TeO), a retinal-recipient target, progressively decreases from 30-90 dpf, whereas investment is relatively consistent across all stages for the midbrain torus semicircularis (TS), a secondary auditory and mechanosensory lateral line center, and the olfactory bulb (OB), a direct target of the olfactory epithelium. In sum, increased investment in higher order integration centers (telencephalon, TL) occurs as juveniles reach adulthood and exhibit more complex cognitive tasks, whereas investment in modality-dominant regions occurs in earlier stages (TeO) or is relatively consistent across development (TS, OB). Complete optical access throughout Danionellas lifespan provides a unique opportunity to investigate how changing brain structure over development correlates with changes in connectivity, microcircuitry, or behavior.

neuroscience↗

bioRxiv2024

Wheat TaNADPO promotes spot blotch resistance

Bipolaris sorokiniana is a common soil-borne fungal pathogen that can infect various organs of wheat (Triticum aestivum L.), causing diseases such as spot blotch, common root rot, head blight, and black point. The genetic basis of wheat resistance to B. sorokiniana is not yet fully understood. In this study, a natural population of 1,302 global common wheat germplasms was established and inoculated with B. sorokiniana at the seedling stage in a greenhouse. Resistance to spot blotch was assessed, revealing that only about 3.8% of the germplasms exhibited moderate or higher resistance levels. A genome-wide association study (GWAS) using high-density 660K single nucleotide polymorphism (SNP) data identified a region on chromosome 1BL (621.2-674.0 Mb) with 9 SNPs significantly associated (p < 10e-4) with spot blotch resistance, designated as Qsb.hebau-1BL. RNA sequencing and qRT-PCR assays showed that the gene TraesCS1B02G410300, encoding nicotinamide-adenine dinucleotide phosphate-binding oxidoreductase (TaNADPO), was significantly induced by B. sorokiniana. Five SNP variations were found in the promoter region of TaNADPO in wheat lines with or without Qsb.hebau-1BL. Transient expression of TaNADPO in Nicotiana benthamiana leaves showed a cytoplasmic subcellular localization of the fusion protein with a green fluorescent protein (GFP) tag. Wheat transgenic lines overexpressing TaNADPO exhibited significantly enhanced resistance to spot blotch compared to wildtype plants, with higher accumulation of reactive oxygen species (ROS). The knockout EMS mutant of Triticum turgidum NADPO (tdnadpo-K2561, Gln125*) showed significantly reduced resistance to spot blotch and lower ROS accumulation compared to wildtype plants. In summary, TaNADPO has been identified as a crucial gene for resistance to B. sorokiniana, providing valuable insights for developing spot blotch-resistant wheat varieties through molecular breeding techniques.

genetics↗

bioRxiv2024

Mild neonatal hypoxia disrupts adult hippocampal learning and memory and is associated with CK2-mediated dysregulation of synaptic calcium-activated potassium channel KCNN2

ObjectiveAlthough nearly half of preterm survivors display persistent neurobehavioral dysfunction including memory impairment without overt gray matter injury, the underlying mechanisms of neuronal or glial dysfunction, and their relationship to commonly observed cerebral white matter injury are unclear. We developed a mouse model to test the hypothesis that mild hypoxia during preterm equivalence is sufficient to persistently disrupt hippocampal neuronal maturation related to adult cellular mechanisms of learning and memory. Methods: Neonatal (P2) mice were exposed to mild hypoxia (8%O2) for 30 min and evaluated for acute injury responses or survived until adulthood for assessment of learning and memory and hippocampal neurodevelopment. ResultsNeonatal mild hypoxia resulted in clinically relevant oxygen desaturation and tachycardia without bradycardia and was not accompanied by cerebral gray or white matter injury. Neonatal hypoxia exposure was sufficient to cause hippocampal learning and memory deficits and abnormal maturation of CA1 neurons that persisted into adulthood. This was accompanied by reduced hippocampal CA3-CA1 synaptic strength and LTP and reduced synaptic activity of calcium-sensitive SK2 channels, key regulators of spike timing dependent neuroplasticity, including LTP. Structural illumination microscopy revealed reduced synaptic density, but intact SK2 localization at the synapse. Persistent loss of SK2 activity was mediated by altered casein kinase 2 (CK2) signaling. InterpretationClinically relevant mild hypoxic exposure in the neonatal mouse is sufficient to produce morphometric and functional disturbances in hippocampal neuronal maturation independently of white matter injury. Additionally, we describe a novel persistent mechanism of potassium channel dysregulation after neonatal hypoxia. Collectively our findings suggest an unexplored explanation for the broad spectrum of neurobehavioral, cognitive and learning disabilities that paradoxically persist into adulthood without overt gray matter injury after preterm birth.

neuroscience↗

bioRxiv2024

Metabolic conservation by protein quality control in Campylobacter jejuni underlies the antibiotic tolerance

Bacterial persistence enables survival during lethal antibiotic exposure and is implicated in recurrent infections, yet the physiology underlying bacterial persistence in many pathogens remains poorly defined. Here we show that exposure of Campylobacter jejuni to ampicillin or ciprofloxacin generates an antibiotic-persistent subpopulation. Rather than undergoing global metabolic shutdown, persister cells adopted a metabolically constrained state characterized by selective maintenance of oxidative phosphorylation and bioenergetic metabolism through coordinated proteostasis control. The ATP-dependent protease ClpP was essential for entry into this persistent state. Loss of ClpP disrupted proteostasis of the electron transport chain, specifically impaired bd-like terminal oxidase integrity, and reduced survival in vivo and in macrophages. These findings identify ClpP-dependent maintenance of redox and bioenergetic homeostasis as critical determinants of C. jejuni persistence and highlight metabolic remodeling as a defining feature of antibiotic tolerance. These insights may inform future therapeutic strategies aimed at disrupting persistence and improving antibiotic efficacy.

microbiology↗

bioRxiv2024

De novo synthesis of fatty acids in Archaea via an archaeal fatty acid synthase complex

Archaea synthesize membranes using isoprenoid-based ether lipids, whereas Bacteria and Eukarya use fatty acid-based ester lipids. While the factors responsible for this "lipid divide" remain unclear, this has important implications for understanding the evolutionary history of eukaryotes, which likely originated from within the Archaea and therefore changed membrane composition from isoprenoid-based to fatty acid-based lipids. Here, using 13C labelling studies, we demonstrate that the archaeal model organisms Sulfolobus acidocaldarius and Haloferax volcanii are capable of de novo fatty acid synthesis. Biochemical characterization and in vitro pathway reconstitution identify the key enzymes of a newly proposed fatty acid synthesis pathway in S. acidocaldarius and show that ketothiolase, ketoacyl-CoA reductase, and hydroxyacyl-CoA dehydratase form a stable assembly mediated by a DUF35 domain protein, which represents the first characterization of an archaeal fatty acid synthase complex. The final step is catalysed by an NADPH-dependent enoyl-CoA reductase. Deletion of the enoyl-CoA reductase demonstrate that this pathway operates in vivo in S. acidocaldarius. The presented results including phylogenetic analysis reveal that the potential to synthesize fatty acids is widespread across archaeal lineages. Collectively, our findings demonstrate that archaea are capable of synthesizing fatty acids, elucidate the molecular mechanisms involved in this process and provide additional insights into the evolutionary histories of fatty acid synthesis in archaea.

microbiology↗

bioRxiv2024

Phosphorylation-Dependent Activation of the bHLH Transcription Factor ICE1/SCRM Promotes Polarization of the Arabidopsis Zygote

Asymmetric cell divisions are a key mechanism for breaking symmetry and orchestrating different cell identities in multicellular organisms. In Arabidopsis thaliana, as in most flowering plants, the first zygotic cell division is asymmetric, giving rise to the embryo proper and an extraembryonic suspensor. Zygotic polarization and differential cell identities in the daughter cells are controlled by the ERECTA-YODA pathway, a prototype receptor kinase-MAP kinase signaling pathway. This pathway also controls asymmetric cell divisions in the epidermis during stomatal development. In this context, the bHLH transcription factor ICE1/SCRM is a direct target of MPK3/6, and phosphorylation negatively controls SCRM activity by targeting the protein for proteasomal degradation. This raises the question if this regulatory module is also involved in the asymmetric division of the zygote. Our results show that SCRM has a critical function in zygote polarization and acts in parallel with the known MPK3/6 target WRKY2 in activating the homeobox transcription factor gene WOX8. Our work further demonstrates that SCRM activity in the early embryo is positively controlled by MPK3/6-mediated phosphorylation. Therefore, the mode of MAP kinase regulation of the same target protein fundamentally differs between the embryo and the epidermis, shedding light on cell type-specific, differential gene regulation by common signaling pathways.

plant biology↗

bioRxiv2024

An Artificial Intelligence Model for Profiling the Landscape of Antigen-binding Affinities of Massive BCR Sequencing Data

The interaction between antigens and antibodies (B cell receptors, BCRs) is the key step underlying the function of the humoral immune system in cancers and other biological contexts. The capability to profile the landscape of antigen-binding affinities of a vast number of BCRs will provide a powerful tool to reveal novel insights at unprecedented levels and will yield powerful tools for translational development. However, current experimental approaches for detecting antibody-antigen interactions are costly and time-consuming, and can only achieve low-to-mid throughput. On the other hand, bioinformatics tools in the field of antibody informatics mostly focus on optimization of antibodies given known binding antigens, which is a very different research question and of limited scope. In this work, we developed an innovative Artificial Intelligence tool, Cmai, to address the prediction of binding between antibodies and antigens that can be scaled to high-throughput sequencing data. We devised a biomarker metric based on the output from Cmai applied to high-throughput BCR sequencing data to predict the landscape of the antigen-binding affinities of the BCRs. We found that extracellular antigens on malignant tumor cells are inducing B cell infiltrations, and the infiltrating B cells have a greater tendency to co-localize with tumor cells expressing these antigens. We further found that the abundance of tumor antigen-targeting antibodies is predictive of immune-checkpoint inhibitor (ICI) treatment response. On the other hand, we found that, during immune-related adverse events (irAEs) caused by ICI treatment, humoral immunity is preferentially responsive to intracellular antigens from the organs affected by the irAEs. Overall, we developed a powerful tool for elucidating the antigen binding landscape of BCR repertoires, and it shall also propell antibody-centric translational applications for cancers and other diseases.

immunology↗

bioRxiv2024

Functional analysis of ESRP1/2 gene variants and CTNND1 isoforms in orofacial cleft pathogenesis

Orofacial cleft (OFC) is a common human congenital anomaly. Epithelial-specific RNA splicing regulators ESRP1 and ESRP2 regulate craniofacial morphogenesis and their disruption result in OFC in zebrafish, mouse and humans. Using esrp1/2 mutant zebrafish and murine Py2T cell line models, we functionally tested the pathogenicity of human ESRP1/2 gene variants. We found that many variants predicted by in silico methods to be pathogenic were functionally benign. Esrp1 also regulates the alternative splicing of Ctnnd1 and these genes are co-expressed in the embryonic and oral epithelium. In fact, over-expression of ctnnd1 is sufficient to rescue morphogenesis of epithelial-derived structures in esrp1/2 zebrafish mutants. Additionally, we identified 13 CTNND1 variants from genome sequencing of OFC cohorts, confirming CTNND1 as a key gene in human OFC. This work highlights the importance of functional assessment of human gene variants and demonstrates the critical requirement of Esrp-Ctnnd1 acting in the embryonic epithelium to regulate palatogenesis.

genetics↗

bioRxiv2024

Electrical and G-protein Regulation of CaV2.2 (N-type) Channels

How G-proteins inhibit N-type, voltage-gated, calcium-selective channels (CaV2.2) during presynaptic inhibition is a decades-old question. G-proteins G{beta}{gamma} bind to intracellular CaV2.2 regions, but the inhibition is voltage-dependent. Using the hybrid electrophysiological and optical approach voltage-clamp fluorometry, we show that G{beta}{gamma} acts by selectively inhibiting a subset of the four different CaV2.2 voltage-sensor domains (VSDs I-IV). During regular "willing" gating, VSDs I and IV activation resemble pore opening, VSD III activation is hyperpolarized, and VSD II appears unresponsive to depolarization. In the presence of G{beta}{gamma}, CaV2.2 gating is "reluctant": pore opening and VSD-I activation are strongly and proportionally inhibited, VSD IV is modestly inhibited while VSD III is not. We propose that G{beta}{gamma} inhibition of VSD-I and -IV underlies reluctant CaV2.2 gating and subsequent presynaptic inhibition.

neuroscience↗