Upregulation of the P2X7 receptor promotes Ca2+ accumulation and inflammatory response in post-stroke depression.
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ABSTRACT:
SUBMITTER: Shen L
PROVIDER: S-EPMC8507060 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:P2X7 receptors are non-selective cation channels that are activated by extracellular ATP and play important roles in inflammation. They differ from other P2X family members by a large intracellular C-terminus that mediates diverse signaling processes that are little understood. A recent cryo-EM study revealed that the C-terminus of the P2X7 receptor forms a unique cytoplasmic ballast domain that possesses a GDP-binding site as well as a dinuclear Zn2+ site. However, the molecular basis for the regulatory function of the ballast domain as well as the interplay between the various ligands remains unclear. Here, we successfully expressed a soluble trimeric P2X7 ballast domain (P2X7BD) and characterized its ligand binding properties using a biophysical approach. We identified calmodulin-binding regions within the ballast domain and found that binding of Ca2+-calmodulin (Ca2+-CaM) and GDP to P2X7BD have opposite effects on its stability. Small-angle X-ray scattering (SAXS) experiments indicate that Ca2+-CaM binding disrupts the trimeric state of P2X7BD. Our results provide a possible framework for the intracellular regulation of the P2X7 receptor.
| S-EPMC9574498 | biostudies-literature
Project description:ObjectiveSleep disturbance and depression are common in stroke patients, however, little is known about the role of sleep in post-stroke depression. This study examined the association between pre-stroke sleep duration and depression at 90 days post-stroke in a population-based bi-ethnic sample.MethodsThe study included 1369 stroke patients from the Brain Attack Surveillance in Corpus Christi project who survived 90 days post-stroke. Depression at 90 days post-stroke was assessed by the 8-item Patient Health Questionnaire, and pre-stroke sleep duration was self-reported shortly after stroke in reference to the pre-stroke state. Multiple imputation and inverse probability weighting were used to deal with missing data and attrition. Weighted logistic regression models were fit to examine the association between pre-stroke sleep duration and post-stroke depression.ResultsThe mean age was 68.2 years, and 63.6% were Mexican American. The prevalence of post-stroke depression was highest among participants reporting less than 6 hours of sleep before stroke (52.4%, 95% confidence interval = 45.7%-59.0%). Compared with participants reporting 7-8 hours of sleep before stroke, those with short sleep duration had significantly increased odds for post-stroke depression (odds ratio = 1.96; 95% confidence interval = 1.38-2.79), after adjustment for sociodemographic, stroke and pre-stroke characteristics including pre-stroke depression.ConclusionsPre-stroke short sleep duration may be an independent risk factor for post-stroke depression.
| S-EPMC7667889 | biostudies-literature
Project description:BackgroundMounting evidence strongly uncovered that peripheral immuno-inflammatory response induced by acute stroke is associated with the appearance of post-stroke depression (PSD), but the mechanism remains unclear.Methods103 stroke patients were assessed at 2 weeks after onset using Diagnostic and Statistical Manual of Mental Disorders, 5th edition and then divided into PSD and non-PSD groups. Polymorphisms of inflammatory molecules (interleukin [IL]-1β, IL-6, IL-10, IL-18, tumor necrosis factor-α [TNF-α], interferon-γ [IFN-γ] and C-reactive protein [CRP]), complete blood count parameters, splenic attenuation (SA) and splenic volume (SV) on unenhanced chest computed tomography, demographic and other clinical characteristics were obtained. Binary logistic regression model was used to analyze the associations between inflammation-related factors and the occurrence of PSD at 2 weeks after stroke.Results49 patients were diagnosed with PSD at 2 weeks after onset (early-onset PSD). The C/T genotypes of CRP rs2794520 and rs1205 were less in PSD group than non-PSD group (both adjusted odds ratio = 3.364; 95%CI: 1.039-10.898; p = 0.043). For CRP rs3091244, the frequency of G allele was higher (80.61% vs. 13.89%) while the frequency of A allele was lower (6.12% vs. 71.30%) in PSD patients than non-PSD patients (χ2 = 104.380; p<0.001). SA of PSD patients was lower than that of non-PSD patients in the presence of CRP rs2794520 C/T genotype and rs1205 C/T genotype (both t = 2.122; p = 0.039). Peripheral monocyte count was less in PSD group than non-PSD group (adjusted odds ratio = 0.057; 95%CI: 0.005-0.686; p = 0.024).ConclusionsCRP polymorphisms, SA based on CRP genotype, and peripheral monocytes are associated with the risk of early-onset PSD, suggesting peripheral immuno-inflammatory activities elicited by stroke in its aetiology.
| S-EPMC9549963 | biostudies-literature
Project description:After the onset of stroke, many patients suffer from emotional behavior changes. Approximately, one-third of stroke survivors are affected by post-stroke depression (PSD), making it a serious social and public health problem. Post-stroke depression (PSD) has an important impact on the course, recovery, and prognosis of stroke. The pathogenesis of PSD is very complex, involving many factors such as biological mechanism and social psychological mechanisms. This article provides a brief review of the hot issues related to etiologies of PSD.
| S-EPMC6351464 | biostudies-literature
Project description:Synapsin I (SynI) is a synaptic vesicle (SV)-associated phosphoprotein that modulates neurotransmission by controlling SV trafficking. The SynI C-domain contains a highly conserved ATP binding site mediating SynI oligomerization and SV clustering and an adjacent main Ca2+ binding site, whose physiological role is unexplored. Molecular dynamics simulations revealed that the E373K point mutation irreversibly deletes Ca2+ binding to SynI, still allowing ATP binding, but inducing a destabilization of the SynI oligomerization interface. Here, we analyzed the effects of this mutation on neurotransmitter release and short-term plasticity in excitatory and inhibitory synapses from primary hippocampal neurons. Patch-clamp recordings showed an increase in the frequency of miniature excitatory postsynaptic currents (EPSCs) that was totally occluded by exogenous Ca2+ chelators and associated with a constitutive increase in resting terminal Ca2+ concentrations. Evoked EPSC amplitude was also reduced, due to a decreased readily releasable pool (RRP) size. Moreover, in both excitatory and inhibitory synapses, we observed a marked impaired recovery from synaptic depression, associated with impaired RRP refilling and depletion of the recycling pool of SVs. Our study identifies SynI as a novel Ca2+ buffer in excitatory terminals. Blocking Ca2+ binding to SynI results in higher constitutive Ca2+ levels that increase the probability of spontaneous release and disperse SVs. This causes a decreased size of the RRP and an impaired recovery from depression due to the failure of SV reclustering after sustained high-frequency stimulation. The results indicate a physiological role of Ca2+ binding to SynI in the regulation of SV clustering and trafficking in nerve terminals.
| S-EPMC9678998 | biostudies-literature
Project description:The endoplasmic reticulum (ER) contains various enzymes that metabolize fatty acids (FAs). Given that FAs are the components of membranes, FA metabolic enzymes might be associated with regulation of ER membrane functions. However, it remains unclear whether there is the interplay between FA metabolic enzymes and ER membrane proteins. Trans-2-enoyl-CoA reductase (TER) is an FA reductase present in the ER membrane and catalyzes the last step in the FA elongation cycle and sphingosine degradation pathway. Here we identify sarco(endo)plasmic reticulum Ca2+-ATPase 2b (SERCA2b), an ER Ca2+ pump responsible for Ca2+ accumulation in the ER, as a TER-binding protein by affinity purification from HEK293 cell lysates. We show that TER directly binds to SERCA2b by in vitro assays using recombinant proteins. Thapsigargin, a specific SERCA inhibitor, inhibits this binding. TER binds to SERCA2b through its conserved C-terminal region. TER overexpression suppresses SERCA2b ATPase activity in microsomal membranes of HEK293 cells. Depletion of TER increases Ca2+ storage in the ER and accelerates SERCA2b-dependent Ca2+ uptake to the ER after ligand-induced Ca2+ release. Moreover, depletion of TER reduces the Ca2+-dependent nuclear translocation of nuclear factor of activated T cells 4. These results demonstrate that TER is a negative regulator of SERCA2b, implying the direct linkage of FA metabolism and Ca2+ accumulation in the ER.
| S-EPMC7949109 | biostudies-literature
Project description:Antimalarials have demonstrated beneficial effects in Systemic Lupus Erithematosus and Rheumatoid Arthritis. However, the mechanisms and the molecular players targeted by these drugs remain obscure. Although hydroxychloroquine (HCQ) is a known ion channel inhibitor, this property has not been linked to its anti-inflammatory effects. We aimed to study whether HCQ inhibits pro-inflammatory ion channels. Electrophysiology experiments demonstrated that HCQ inhibited Ca++-activated K+ conductance in THP-1 macrophages in a dose-dependent manner. In macrophages, ATP-induced K+ efflux plays a key role in activating the NLRP3 inflammasome. ATP-induced IL-1beta secretion was controlled by the KCa1.1 inhibitor iberiotoxin. NS1619 and NS309 (KCa1.1 and KCa3.1 activators respectively) induced the secretion of IL-1beta. This effect was inhibited by HCQ and also by iberiotoxin and clotrimazol (KCa3.1 inhibitor), arguing against off-target effect. In vitro, HCQ inhibited IL-1beta and caspase 1 activation induced by ATP in a dose-dependent manner. HCQ impaired K+ efflux induced by ATP. In vivo, HCQ inhibited caspase 1-dependent ATP-induced neutrophil recruitment. Our results show that HCQ inhibits Ca++-activated K+ channels. This effect may lead to impaired inflammasome activation. These results are the basis for i) a novel anti-inflammatory mechanism for HCQ and ii) a new strategy to target pro-rheumatic Ca++-activated K+ channels.
| S-EPMC5432501 | biostudies-literature
Project description:Huntington's disease (HD) is a fatal degenerative disorder affecting the nervous system. It is characterized by motor, cognitive, and psychiatric dysfunctions, with a late onset and an autosomal dominant pattern of inheritance. HD-causing mutation consists in an expansion of repeated CAG triplets in the huntingtin gene (HTT), encoding for an expanded polyglutamine (polyQ) stretch in the huntingtin protein (htt). The mutation causes neuronal dysfunction and loss through multiple mechanisms, affecting both the nucleus and cytoplasm. P2X7 receptor (P2X7R) emerged as a major player in neuroinflammation, since ATP - its endogenous ligand - is massively released under this condition. Indeed, P2X7R stimulation in the central nervous system (CNS) is known to enhance the release of pro-inflammatory cytokines from microglia and of neurotransmitters from neuronal presynaptic terminals, as well as to promote apoptosis. Previous experiments performed with neurons expressing the mutant huntingtin and exploiting HD mouse models demonstrated a role of P2X7R in HD. On the basis of those results, here, we explore for the first time the status of P2X7R in HD patients' brain. We report that in HD postmortem striatum, as earlier observed in HD mice, the protein levels of the full-length form of P2X7R, also named P2X7R-A, are upregulated. In addition, the exclusively human naturally occurring variant lacking the C-terminus region, P2X7R-B, is upregulated as well. As we show here, this augmented protein levels can be explained by elevated mRNA levels. Furthermore, in HD patients' striatum, P2X7R shows not only an augmented total transcript level but also an alteration of its splicing. Remarkably, P2X7R introns 10 and 11 are more retained in HD patients when compared with controls. Taken together, our data confirm that P2X7R is altered in brains of HD subjects and strengthen the notion that P2X7R may represent a potential therapeutic target for HD.
| S-EPMC7573237 | biostudies-literature
Project description:BackgroundLittle is known about ethnic differences in poststroke depression (PSD) in the United States. This study aims to estimate the prevalence of PSD at 90 days after first-ever stroke and to examine ethnic differences in the prevalence between Mexican Americans (MAs) and non-Hispanic whites (NHWs).Methods and resultsStroke cases from 2011 to 2015 were identified from the BASIC project (Brain Attack Surveillance in Corpus Christi)-a population-based stroke surveillance study in south Texas. Participants were interviewed at the onset of stroke (baseline interview) and ≈90 days post-stroke (outcome interview). PSD was assessed by the Patient Health Questionnaire-8. Inverse probability weights were generated to account for differential attrition, and weighted logistic regression was used to investigate the association between ethnicity and PSD. The study sample consisted of 586 first-ever stroke patients who completed nonproxy baseline and outcome interviews and had depression assessment. Approximately, 60% of them were MAs, and 40% were NHWs. After accounting for attrition, the prevalence of depression at 90 days post-stroke was 30.4% for MAs (95% confidence interval, 25.0%-35.9%) and 20.7% for NHWs (95% confidence interval, 15.7%-25.7%). The crude odds of PSD in MAs was 1.69 times greater than that in NHWs (95% confidence interval, 1.13-2.51). The odds ratio decreased by 23.6% after adjustment for education (odds ratio, 1.29; 95% confidence interval, 0.82-2.02) and was further attenuated with additional adjustment for other covariates.ConclusionsMAs had a higher prevalence of PSD at 90 days than NHWs. The ethnic difference was explained by sociodemographic and health factors, especially low educational attainment.
| S-EPMC5788032 | biostudies-literature
Project description:Moderate-intensity exercise can help delay the development of osteoarthritis (OA). Previous studies have shown that the purinergic receptor P2X ligand gated ion channel 7 (P2X7) is involved in OA development and progression. To investigate the effect of exercise on P2X7 activation and downstream signaling in OA, we used the anterior cruciate ligament transection (ACLT)-induced OA rat model and primary chondrocyte culture system. Our in vivo experiments confirmed that treadmill exercise increased P2X7 expression and that this effect was more pronounced at the later time points. Furthermore, P2X7 activation induced endoplasmic reticulum (ER) stress and increased the expression levels of ER stress markers, such as 78 kDa glucose-regulated protein (GRP78), protein kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme-1 (IRE1), and activating transcription factor 6 (ATF6). At the early time points, IRE1 and PERK were activated, and mTOR was inhibited. At the later time points, mTOR was activated, mediating PERK to promote ER stress-apoptosis, whereas IRE1 and autophagy were inhibited. To confirm our observations in vitro, we treated primary chondrocytes with the P2X7 agonist benzoylbenzoyl-ATP (Bz-ATP). Our results confirmed that P2X7-mediated Ca2+ influx activated IRE1-mediated autophagic flux and induced PERK-mediated ER stress-apoptosis. To further investigate the role of P2X7 in OA, we injected mTOR antagonist rapamycin or P2X7 antagonist A740003 into the knee joints of ACLT rats. Our results demonstrated that mTOR inhibition induced autophagy, decreased apoptosis, and reduced cartilage loss. However, injection of mTOR agonist MHY1485 or Bz-ATP had the opposite effect. In summary, our results indicated that during the early stages of moderate-intensity exercise, P2X7 was activated and autophagic flux was increased, delaying OA development. At the later stages, P2X7 became over-activated, and the number of apoptotic cells increased, promoting OA development. We propose that the IRE1-mTOR-PERK signaling axis was involved in the regulation of autophagy inhibition and the induction of apoptosis. Our findings provide novel insights into the positive and preventative effects of exercise on OA, suggesting that the intensity and duration of exercise play a critical role. We also demonstrated that on a molecular level, P2X7 and its downstream pathways could be potential therapeutic targets for OA.
| S-EPMC8248364 | biostudies-literature