Biology subjects

Qin, M.

Publications and source records attributed to Qin, M..

At least 19 recordsLinked to original sources

bioRxiv2026

A bacterial Rhesus transporter retunes a structurally conserved ammonium pore into a reversible nitrogen valve

How conserved proteins acquire new physiological functions is a central question in molecular evolution. Rather than inventing new architectures, evolution often repurposes existing scaffolds, preserving core structural features while retuning the molecular logic that connects mechanism to physiology. Membrane transporters offer a powerful test of this principle because substrate selectivity, directionality, flux and energetic cost must be coordinated at the interface between the cell and its environment. The Amt/Mep/Rh superfamily controls one of the most fundamental requirements of cellular life: the movement of reduced nitrogen across biological membranes. Despite sharing a highly conserved ammonium-conducting pore, these proteins support distinct physiological roles, including nitrogen acquisition, sensing and homeostatic control. Here, we combined targeted mutagenesis, electrophysiology, yeast complementation and molecular dynamics simulations to define the transport logic of NeRh50, a bacterial Rhesus protein from the ammonia-oxidising bacterium Nitrosomonas europaea. We show that NeRh50 is not simply an AmtB-like ammonium importer. Instead, it uses the conserved Amt/Mep/Rh pore as a branched transport system in which inward uptake and export-linked transport can be separated genetically and mechanistically. Two conserved pore residues define this division of labour. A residue at the external entrance couples ammonium recruitment to productive inward uptake, whereas a second residue deeper in the pore enables a distinct transport mode required for substrate release when intracellular nitrogen accumulates. Thus, conserved Amt/Mep/Rh pore landmarks do not impose a single mechanism. Their local chemistry can be reassigned to generate different transport outputs, allowing NeRh50 to function as a reversible nitrogen valve. These findings reveal how minimal retuning within an ancient membrane-protein scaffold can rewire transport directionality and adapt nitrogen handling to ecological and physiological demand.

biochemistry↗

bioRxiv2026

Vitamin D3 attenuates nitrogen mustard-induced dermal toxicity by enhancing microbial butyrate production via the intestinal VDR-α-defensin signaling pathway

Nitrogen mustard (NM)-caused severe cutaneous damage lacks effective targeted therapies. Vitamin D3 (VD3) shows promise as a therapy for NM-induced dermal toxicity; however, the underlying mechanisms remain elusive. Herein, we initially confirmed that NM induced gut flora dysbiosis, characterized by a decrease of Akkermansia muciniphila (AKK) abundance, thereby leading to butyrate reduction. Antibiotics (ABX) significantly promoted NM-induced skin injury, whereas fecal microbiota transplantation of the controls feces (HC-FMT) or AKK administration attenuated NM-induced dermal toxicity. HC-FMT or AKK significantly increased butyrate levels in feces and serum of NM-treated mice. Butyrate notably attenuated ABX-caused acceleration of NM-induced skin injury. Meanwhile, NM markedly decreased the expression of -defensins, MMP7, and VDR. NM failed to further decrease AKK abundance and BA contents in intestinal MMP7-deficient mice, which was abolished by human alpha defensin 5 (HD5) overexpression. And intestinal MMP7 deficiency enhanced NM-caused skin injury, which was markedly attenuated by HD5 overexpression, AKK transplantation, or BA supplementation. Moreover, NM also failed to further reduce MMP7 and -defensin expression, AKK abundance, and butyrate levels in intestinal VDR-silenced mice. Finally, VD3 remodeled the gut microbiome particularly enriching AKK, increased butyrate contents and promoted the expression of -defensins, MMP7, and VDR, thereby attenuating NM-induced skin damage. The protective effect of VD3 against NM-caused dermal toxicity was abolished by either ABX or intestinal-specific knockdown of MMP7 or VDR in mice; however, this impairment was reversed by butyrate or AKK. In conclusion, VD3 attenuated NM-caused dermal toxicity by promoting BA production via remodeling the gut microbiota, and this effect was partially mediated by the intestinal VDR--defensin signaling pathway. These highlight that targeting the gut flora or supplementing with BA could be potential therapies for NM-induced dermal toxicity.

molecular biology↗

bioRxiv2025

In situ generated vaccine-like pyroptosome for personalized cancer immunotherapy

The efficacy of in situ cancer vaccination has been hampered by poor spatiotemporal orchestration of multiple key steps of cancer-immunity cycle in most tumours and systemic toxicity related to therapeutic strategies. Here, we report a systemic injectable and pyroptosis-enabled nanoadjuvant (SPEN) that precisely evokes the secretion of vaccine-like pyroptosome in tumour area for eliciting robust anti-tumour immunity. SPEN induces vigorous immunogenic pyroptosis, triggering the efficient release of tumour antigen-rich pyroptosomes, DAMPs, and proinflammatory cytokines. Upon the activatable release of a TLR7/8 agonist into pyroptosome, the generated pyroptosome functions as in situ cancer vaccine for cooperatively activating the cancer-immunity cycle while avoiding systemic toxicity. This in situ vaccine boosts both innate and adaptive immune response, facilitating the eradication of primary tumour and long-lasting cancer prevention. Our findings provide new insights into the rational design of pyroptosis-inducing nanomedicines for boosting the cancer-immunity cycle, thus advancing personalized cancer immunotherapy.

cancer biology↗

bioRxiv2025

Cerebellar climbing fibers convey perceptual choice during decision-making

Cerebellar climbing fibers are thought to signal reward prediction errors in non-motor functions. By imaging postsynaptic responses of climbing fibers onto mouse Purkinje cell dendrites during auditory discrimination, we found that climbing fibers in crus I can encode cue identities or perceptual choices. These responses were reshaped by reversal learning. Optogenetic perturbation of climbing fiber activity impaired discrimination. These results suggest a feedforward role of climbing fibers in perceptual decision-making.

neuroscience↗

bioRxiv2024

Identification and genomic characterization of a novel bisegmented coronavirus in the lesser panda

Coronaviruses (CoVs) are enveloped positive-sense single-stranded RNA viruses and are renowned for their capacity to infect a diverse range of animals, including humans. In this study, we report the identification and characterization of a novel bisegmented coronavirus, designated LpCoV, from a dead lesser panda, which exhibited severe clinical manifestations and lesions in multiple organs. The LpCoV represents the first documented coronavirus with a unique bisegmented genome while maintaining the typical coronavirus morphology. One genomic segment encodes the ORF1ab polyprotein, while the other segment encodes the spike and nucleocapsid proteins, notably lacking the envelope (E) and membrane (M) genes. The pairwise patristic distances of the five concatenated domains in the replicase region (3CLpro, NiRAN, RdRP, ZBD, and HEL1) between LpCoV and -{delta} coronaviruses range from 1.19 to 1.70. Based on the classification criteria established by the International Committee on Taxonomy of Viruses (ICTV), LpCoV is proposed to constitute a new genus within the Coronaviridae family. An epidemiological investigation identified five LpCoV-like viruses in lesser pandas from two different provinces (Sichuan and Jiangsu) indicating the long-term circulation and expansion of bisegmented coronaviruses in wildlife. These findings highlight the imperative for comprehensive viral surveillance in wildlife, which is essential for understanding and mitigating the risk of animal diseases and zoonotic spillover.

microbiology↗

bioRxiv2024

Multi-purpose controllable protein generation via prompted language models

Deep learning is increasingly powerful for designing proteins that meet structural and functional requirements. However, most existing methods follow a conventional pipeline: first defining a backbone structure and then generating sequences consistent with it. This approach, which encodes all design goals indirectly through structures, restricts flexibility and struggles to address multiple, complex design objectives simultaneously. We present PROPEND, a multi-purpose protein sequence design method based on the "pre-train and prompt" framework. We show PROPENDs broad utility and accuracy both in silico and in vitro by directly controlling multiple properties through the prompt of backbones, blueprints, functional tags, and their combinations. For the five sequences tested with in vitro experiments, PROPEND achieved a maximum functional recovery of 105.2%, significantly outperforming the classical design pipelines 50.8%.

synthetic biology↗

bioRxiv2024

Cross-tissue Graph Attention Networks for Semi-supervised Gene Expression Prediction

High-throughput biotechnologies have significantly advanced precision medicine by enabling the exploitation of global gene expression patterns to enhance our understanding of disease etiology, progression, and treatment options. However, the tissue-specific nature of gene expression presents a challenge, particularly for less accessible tissues such as the brain, underscoring the need for computational methods to accurately impute gene expression in these critical but hard-to-reach tissues. While several attempts to impute gene expression in tissue-specific contexts have shown promising results, their reliance on regression analysis faces limitations due to the inability to capture complex, nonlinear relationships in gene expression patterns. In contrast, modern machine learning techniques, particularly graph neural networks, have demonstrated superior performance by efficiently modeling the intricate interactions among genes across different tissues. Therefore, we introduce gene expression imputation with Graph Attention Networks (gemGAT), a novel approach leveraging Graph Attention Networks (GATs) to enhance gene expression prediction across different tissues. gemGAT distinguishes itself by predicting the expression of all genes simultaneously, utilizing the full spectrum of genomic data to account for gene co-expressions and non-linear relationships. Validated through extensive experiments with Genotype-Tissue Expression (GTEx) data and a case study from the Alzheimers Disease Neuroimaging Initiative (ADNI), gemGAT demonstrates superior performance over existing methods by efficiently capturing non-linear gene co-expressions. This advancement underscores gemGATs potential to significantly contribute to precision medicine, showcasing its utility in advancing our understanding of gene expression in less accessible tissues.

bioinformatics↗

bioRxiv2024

Identification and predictive machine learning models construction of gut microbiota associated with lymph node metastasis in colorectal cancer

This study focuses on the significant role between gut microbiota and lymph node metastasis (LNM) in colorectal cancer (CRC). By conducting 16S rRNA sequencing on fecal samples from 147 CRC patients and combining it with the linear discriminant analysis effect size (LEfSe) algorithm, we successfully identified significant differences in the gut microbiota between patients with LNM and those with none lymph node metastasis (NLNM). Furthermore, using transcriptome data from 9 CRC patients, we constructed an immune cell infiltration matrix to deeply explore the biological functions associated with LNM. Eventually, using the characteristics of the gut microbiota associated with LNM, we developed random forest (RF) and multilayer perceptron (MLP) machine learning models to predict the lymph node metastasis status of CRC patients. We identified 21 differentially abundant gut microbes between the two groups, among which Bacteroides plebeius, significantly enriched in LNM group, is closely related to the upregulation of resting NK cells and chemokine CXCL8 expression, and this bacterial species is also positively correlated with the enhancement of fructose metabolism. The RF and MLP models constructed based on the LNM-associated gut microbiota showed good predictive efficacy in predicting LNM status in CRC. This study reveals that Bacteroides plebeius may play an important role in the progression of CRC, with its mechanism potentially involving changes in immune modulation and metabolic pathways. The classification model constructed based on gut microbiota characteristics can predict LNM status of CRC, providing a new perspective for personalized and precision treatment of CRC patients. ImportanceThis study highlights the pivotal role of gut microbiota in lymph node metastasis (LNM) of CRC, identifying key microbial differences between LNM and NLNM patients. Our findings implicate Bacteroides plebeius in CRC progression via immune modulation and metabolic alterations. Moreover, machine learning models based on gut microbiota predict LNM status accurately, offering a novel approach for personalized CRC treatment.

microbiology↗

bioRxiv2024

AMPK agonism optimizes the in vivo persistence and anti-leukemia efficacy of chimeric antigen receptor T cells

BACKGROUNDChimeric antigen receptor T cell (CART) therapy has seen great clinical success. However, up to 50% of leukemia patients relapse and long-term survivor data indicate that CART cell persistence is key to enforcing relapse-free survival. Unfortunately, ex vivo expansion protocols often drive metabolic and functional exhaustion, reducing in vivo efficacy. Preclinical models have demonstrated that redirecting metabolism ex vivo can improve in vivo T cell function and we hypothesized that exposure to an agonist targeting the metabolic regulator AMP-activated protein kinase (AMPK), would create CARTs capable of both efficient leukemia clearance and increased in vivo persistence. METHODSCART cells were generated from healthy human via lentiviral transduction. Following activation, cells were exposed to either Compound 991 or DMSO for 96 hours, followed by a 48-hour washout. During and after agonist treatment, T cells were harvested for metabolic and functional assessments. To test in vivo efficacy, immunodeficient mice were injected with luciferase+ NALM6 leukemia cells, followed one week later by either 991- or DMSO-expanded CARTs. Leukemia burden and anti-leukemia efficacy was assessed via radiance imaging and overall survival. RESULTSHuman T cells expanded in Compound 991 activated AMPK without limiting cellular expansion and gained both mitochondrial density and improved handling of reactive oxygen species (ROS). Importantly, receipt of 991-exposed CARTs significantly improved in vivo leukemia clearance, prolonged recipient survival, and increased CD4+ T cell yields at early times post-injection. Ex vivo, 991 agonist treatment mimicked nutrient starvation, increased autophagic flux, and promoted generation of mitochondrially-protective metabolites. DISCUSSIONEx vivo expansion processes are necessary to generate sufficient cell numbers, but often promote sustained activation and differentiation, negatively impacting in vivo persistence and function. Here, we demonstrate that promoting AMPK activity during CART expansion metabolically reprograms cells without limiting T cell yield, enhances in vivo anti-leukemia efficacy, and improves CD4+ in vivo persistence. Importantly, AMPK agonism achieves these results without further modifying the expansion media, changing the CART construct, or genetically altering the cells. Altogether, these data highlight AMPK agonism as a potent and readily translatable approach to improve the metabolic profile and overall efficacy of cancer-targeting T cells.

immunology↗

bioRxiv2024

Selective regulation of IFN-γ and IL-4 co-producing unconventional T cells by purinergic signalling

Unconventional T cells, including mucosal-associated invariant T (MAIT), natural killer T (NKT), and gamma-delta T ({gamma}{delta}T) cells, comprise distinct T-bet+, IFN-{gamma}+ and ROR{gamma}t+, IL-17+ subsets which play differential roles in health and disease. NKT1 cells are susceptible to ARTC2-mediated P2X7 receptor (P2RX7) activation, but the effects on other unconventional T-cell types are unknown. Here, we show that MAIT, {gamma}{delta}T, and NKT cells express P2RX7 and are sensitive to P2RX7-mediated cell death. Mouse peripheral T-bet+ MAIT1, {gamma}{delta}T1, and NKT1 cells, especially in liver, co-express ARTC2 and P2RX7, which can be further upregulated by retinoic acid. Blocking ARTC2 or inhibiting P2RX7 protected MAIT1, {gamma}{delta}T1, and NKT1 cells from cell death, enhanced their survival in vivo, and increased the number of IFN-{gamma}-secreting cells without affecting IL-17 production. Importantly, this revealed the existence of IFN-{gamma} and IL-4 co-producing unconventional T-cell populations normally lost upon isolation due to ARTC2/P2RX7-induced death. Administering extracellular NAD in vivo activated this pathway, depleting P2RX7-sensitive unconventional T cells. Our study reveals ARTC2/P2RX7 as a common regulatory axis modulating the unconventional T-cell compartment, affecting the viability of IFN-{gamma}- and IL-4-producing T cells, offering important insights to facilitate future studies into how these cells can be regulated in health and disease.

immunology↗

bioRxiv2024

A high-performance genetically encoded sensor for cellular imaging of PKC activity in vivo

We report a genetically encoded fluorescence lifetime sensor for protein kinase C (PKC) activity, named CKAR3, based on Forster resonance energy transfer. CKAR3 exhibits a 10-fold increased dynamic range compared to its parental sensors and enables in vivo imaging of PKC activity during animal behavior. Our results reveal robust PKC activity in a sparse neuronal subset in the motor cortex during locomotion, in part mediated by muscarinic acetylcholine receptors.

neuroscience↗

bioRxiv2024

Cryptic cycling by electroactive bacterioplankton in Trout Bog Lake

The genetic potential for extracellular electron transfer (EET)-based metabolism has been shown to be a prevailing feature of humic lakes where bacterioplankton may be able to use EET to cycle dissolved organic matter (DOM) extracellularly between oxidized and reduced states, but measurable abiotic features resulting from this phenomenon have yet to be demonstrated. We observed an anoxygenic photosynthetic Chlorobium sp. bloom each summer in Trout Bog Lake in northern WI, USA. Given this blooms characteristics, we hypothesized that EET-based metabolisms of Chlorobium sp. and accompanying bacteria cycle DOM between oxidized and reduced states with seasonal or diel-timescale oscillations; therefore, we anticipated this could be measured by weekly and subdaily sampling. We collected vertical profiles on these timescales using a multiparameter sonde, including oxidation-reduction potential measurement, and we assayed for inorganic electron donors. We also developed and deployed a buoy to measure electric current flow between many pairs of electrodes simultaneously. Using metagenomics analyses, we examined the EET genes and other oxidoreductases of bacteria from water column samples at select depths and from biofilms that developed on electrodes at similar depths. Our results indicate the occurrence of diel electron cycling between phototrophic oxidation (electrotrophic metabolism) and anaerobic respiration (electrogenic metabolism), likely involving DOM. We also observed a gradual seasonal increase in hypolimnion oxidation-reduction potential. These diel and seasonal patterns have implications for carbon emissions and the ecology of electroactive bacteria in lakes. IMPORTANCEWe investigated the physical, chemical, and redox characteristics of a bog lake and electrodes hung therein to test the hypothesis that dissolved organic matter is being cycled between oxidized and reduced states by electroactive bacterioplankton powered by phototrophy. To do so we performed field-based analyses on multiple timescales using both established and novel instrumentation. We paired these analyses with recently developed bioinformatics pipelines for metagenomics data to investigate genes that enable electroactive metabolism and accompanying metabolisms. Our results are consistent with our hypothesis and yet upend some of our other expectations. Our findings have implications for understanding greenhouse gas emissions from lakes, including electroactivity as an integral part of lake metabolism throughout more of the anoxic parts of lakes and for a longer portion of the summer than expected. Our results also give a sense of what electroactivity occurs at given depths and provide a strong basis for future studies.

microbiology↗

bioRxiv2024

SLC13A2-transported citrate is a metabolic signal for PKM2 acetylation and degradation to suppress tumor growth

Background and aimsMetabolic reprogramming represents as a pivotal hallmark for cancer, but TCA cycle in tumorigenesis and progression has long been neglected. Solute carrier (SLC) transporters mediate the transport of TCA cycle intermediates across membrane, but their functions in cancer pathogenesis remains unclear. Approaches & ResultsUsing integrated analysis of solute carrier (SLC) transporters for TCA cycle intermediates, we found that SLC13A2 was consistently downregulated in hepatocellular carcinoma (HCC) cells and liver tissues from human patients and heterogeneous mouse models. Adeno-associated virus (AAV)-transduced liver-specific knockout or overexpression of SLC13A2 promoted or ameliorated HCC progression in the primary mouse model, demonstrating that SLC13A2 served as a protective factor during HCC pathogenesis. SLC13A2 inhibited HCC cell proliferation by decreasing mitochondrial function via suppressed oxygen consumption and ATP production. Combined with metabolic flux analysis, we found that SLC13A2 imported citrate, which secreted acetyl-CoA as a precursor for the acetylation of pyruvate kinase muscle isozyme M2 (PKM2), which led to its protein degradation. Decreased activity of pyruvate kinase depleted pyruvate for the TCA cycle, thus inhibiting amino acid synthesis and nucleotide metabolism. Additionally, a decrease in nuclear PKM2 protein transduced to reprogrammed gene transcription for cell proliferation and metabolism which is required for tumor growth. ConclusionsThis study revealed that citrate transported by SLC13A2 acts as a signal to disrupt metabolic homeostasis for tumor growth and suggests potential drug targets for HCC therapy. graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=165 SRC="FIGDIR/small/591017v2_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@80c95eorg.highwire.dtl.DTLVardef@124750corg.highwire.dtl.DTLVardef@809ab4org.highwire.dtl.DTLVardef@12cbe74_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Cryo-electron tomographic investigation of native hippocampal glutamatergic synapses

Chemical synapses are the major sites of communication between neurons in the nervous system and mediate either excitatory or inhibitory signaling [1]. At excitatory synapses, glutamate is the primary neurotransmitter and upon release from presynaptic vesicles, is detected by postsynaptic glutamate receptors, which include ionotropic AMPA and NMDA receptors [2, 3]. Here we have developed methods to identify glutamatergic synapses in brain tissue slices, label AMPA receptors with small gold nanoparticles (AuNPs), and prepare lamella for cryo-electron tomography studies. The targeted imaging of glutamatergic synapses in the lamella is facilitated by fluorescent pre- and postsynaptic signatures, and the subsequent tomograms allow for identification of key features of chemical synapses, including synaptic vesicles, the synaptic cleft and AuNP-labeled AMPA receptors. These methods pave the way for imaging brain regions at high resolution, using unstained, unfixed samples preserved under near-native conditions.

biochemistry↗

bioRxiv2024

Prevalent co-release of glutamate and GABA throughout the mouse brain

Several neuronal populations in the brain transmit both the excitatory and inhibitory neurotransmitters, glutamate, and GABA, to downstream neurons. However, it remains largely unknown whether these opposing neurotransmitters are co-released onto the same postsynaptic neuron simultaneously or are independently transmitted at different time and locations (called co-transmission). Here, using whole-cell patch-clamp recording on acute mouse brain slices, we observed biphasic miniature postsynaptic currents, i.e., minis with time-locked excitatory and inhibitory currents, in striatal spiny projection neurons (SPNs). This observation cannot be explained by accidental coincidence of monophasic miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs, respectively), arguing for the co-release of glutamate and GABA. Interestingly, these biphasic minis could either be an mEPSC leading an mIPSC or vice versa. Although dopaminergic axons release both glutamate and GABA in the striatum, deletion of dopamine neurons did not eliminate biphasic minis, indicating that the co-release originates from another neuronal type. Importantly, we found that both types of biphasic minis were detected in other neuronal subtypes in the striatum as well as in nine out of ten additionally tested brain regions. Our results suggest that co-release of glutamate and GABA is a prevalent mode of neurotransmission in the brain.

neuroscience↗

bioRxiv2023

Alasemenia, the earliest ovule with three wings and without cupule

The ovules or seeds (fertilized ovules) with wings are widespread and especially important for wind dispersal. However, the earliest ovules in the Famennian of the Late Devonian are rarely known about the dispersal syndrome and usually surrounded by a cupule. From Xinhang, Anhui, China, we report a new taxon of Famennian ovules, Alasemenia tria gen. et sp. nov. Each ovule possesses three integumentary wings evidently extending outwards, folding inwards along abaxial side and enclosing most part of nucellus. The ovule is borne terminally on smooth dichotomous branches and lacks a cupule. Alasemenia suggests that the integuments of the earliest ovules without a cupule evolved functions in wind dispersal and probable photosynthetic nutrition. It indicates that the seed wing originated earlier than other wind dispersal mechanisms such as seed plume and pappus, and that three- or four-winged seeds were followed by seeds with less wings. Mathematical analysis shows that three-winged seeds are more adapted to wind dispersal than seeds with one, two or four wings under the same condition.

paleontology↗

bioRxiv2023

RAG1 and RAG2 non-core regions are implicated in the leukemogenesis and off-target V(D)J recombination in BCR-ABL1-driven B cell lineage lymphoblastic leukemia.

The evolutionary conservation of non-core RAG regions suggests significant roles that might involve quantitative or qualitative alterations in RAG activity. Off-target V(D)J recombination contributes to lymphomagenesis and is exacerbated by RAG2 C-terminus absence in Tp53-/- mice thymic lymphomas. However, the genomic stability effects of non-core regions from both cRAG1 and cRAG2 in BCR-ABL1+ Blymphoblastic leukemia (BCR-ABL1+ B-ALL), the characteristics, and mechanisms of non-core regions in suppressing off-target V(D)J recombination remains unclear. Here, we established three mouse models of BCR-ABL1+ B-ALL in mice expressing full-length RAG (fRAG), core RAG1 (cRAG1), and core RAG2 (cRAG2). The cRAG (cRAG1 and cRAG2) leukemia cells exhibited greater malignant tumor characteristics compared to fRAG cells. Additionally, cRAG cells showed higher frequency of off-target V(D)J recombination and oncogenic mutations than fRAG. We also revealed decreased RAG cleavage accuracy in cRAG cells and a smaller recombinant size in cRAG1 cells, which could potentially exacerbate off-target V(D)J recombination in cRAG cells. In conclusion, these findings indicate that the non-core RAG regions, particularly the non-core region of RAG1, play a significant role in preserving V(D)J recombination precision and genomic stability in BCR-ABL1+ B-ALL.

immunology↗

bioRxiv2023

PKA catalytic subunits dissociate from regulatory subunits to regulate neuronal functions

Protein kinase A (PKA) plays essential roles in diverse cellular functions. However, the spatiotemporal dynamics of endogenous PKA upon activation remain debated. The classical model predicts that PKA catalytic subunits dissociate from regulatory subunits in the presence of cAMP, whereas a second model proposes that catalytic subunits remain associated with regulatory subunits following physiological activation. Here we report that different PKA subtypes, as defined by the regulatory subunit, exhibit distinct subcellular localization at rest in CA1 neurons of cultured hippocampal slices. Nevertheless, when all tested PKA subtypes are activated by norepinephrine, presumably via the {beta}-adrenergic receptor, catalytic subunits translocate to dendritic spines but regulatory subunits remain unmoved. These differential spatial dynamics between the subunits indicate that at least a significant fraction of PKA dissociates. Furthermore, PKA-dependent regulation of synaptic plasticity and transmission can be supported only by wildtype, dissociable PKA, but not by inseparable PKA. These results indicate that endogenous PKA regulatory and catalytic subunits dissociate to achieve PKA function in neurons.

cell biology↗