Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA101393 | ENA |
REPOSITORIES: ENA
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Project description:Objective: L-type calcium channels (LTCC) homeostatically regulate calcium on a beat by beat basis, but also provide Ca that over long time scales may contribute to transcriptional regulation. We previously showed that sustained LTCC blockade (CCB) elicits LTCC remodeling in ventricular cardiac myocytes (CM). Here we hypothesize that sustained CCB has broad effects on the expression of genes involved in calcium handling. Methods and Results: Therefore, we subjected adult mice to sustained CCB for 24 hours and performed gene expression profiling. In comparison to vehicle-only control animals, 231 genes were up-regulated, and 111 genes were down-regulated by sustained LTCC blockade (p <0.01). Gene ontology analysis suggested that the CaMKIIdelta signaling pathway was up-regulated in these cells. Unexpectedly, phosphorylation of phospholamban (PLN) at threonine17 (Thr17), an index of CaMKIIdelta activity, was not changed by sustained CCB; however, the degree of phosphorylation of the neighboring PLN-Ser16 substrate site for PKA was significantly reduced by sustained CCB compared to control. Gene expression profiling suggested no change in PKA, but it showed that protein phosphatase 2A (PP2A) mRNA increased, and immunoblots demonstrated that PP2Ac-alpha protein was significantly increased by sustained CCB. Consistent with elevated PP2Ac-alpha protein expression LTCC exhibited decreased phosphorylation of the C-terminal Ser1928 PKA substrate site. Conclusions: We conclude that sustained CCB elicits a spectrum of transcriptional events, including compensatory up-regulation of LTCC and PP2Ac-alpha. Although this study is restricted to mouse, these results suggest the new hypothesis that clinically-relevant sustained LTCC blockade in humans results in changes in gene regulation in the heart. Keywords: L-type calcium channel, calcium channel blockade, verapamil
2009-12-31 | GSE8367 | GEO
Project description:Objective: L-type calcium channels (LTCC) homeostatically regulate calcium on a beat by beat basis, but also provide Ca that over long time scales may contribute to transcriptional regulation. We previously showed that sustained LTCC blockade (CCB) elicits LTCC remodeling in ventricular cardiac myocytes (CM). Here we hypothesize that sustained CCB has broad effects on the expression of genes involved in calcium handling. Methods and Results: Therefore, we subjected adult mice to sustained CCB for 24 hours and performed gene expression profiling. In comparison to vehicle-only control animals, 231 genes were up-regulated, and 111 genes were down-regulated by sustained LTCC blockade (p <0.01). Gene ontology analysis suggested that the CaMKIIdelta signaling pathway was up-regulated in these cells. Unexpectedly, phosphorylation of phospholamban (PLN) at threonine17 (Thr17), an index of CaMKIIdelta activity, was not changed by sustained CCB; however, the degree of phosphorylation of the neighboring PLN-Ser16 substrate site for PKA was significantly reduced by sustained CCB compared to control. Gene expression profiling suggested no change in PKA, but it showed that protein phosphatase 2A (PP2A) mRNA increased, and immunoblots demonstrated that PP2Ac-alpha protein was significantly increased by sustained CCB. Consistent with elevated PP2Ac-alpha protein expression LTCC exhibited decreased phosphorylation of the C-terminal Ser1928 PKA substrate site. Conclusions: We conclude that sustained CCB elicits a spectrum of transcriptional events, including compensatory up-regulation of LTCC and PP2Ac-alpha. Although this study is restricted to mouse, these results suggest the new hypothesis that clinically-relevant sustained LTCC blockade in humans results in changes in gene regulation in the heart. Keywords: L-type calcium channel, calcium channel blockade, verapamil Female and male ICR mice (12-14 weeks age) weighing between 25 and 30 grams were anesthetized with a ketamine/xylazine mixture ( i.p.) allowing the subcutaneous implantation of miniosmotic pumps (Alzet, model 2001). The pumps were filled with either verapamil or vehicle (0.02% ascorbic acid). Control animals carried mini-pumps with vehicle and control animals were investigated in parallel with each set of experimental animals. Mini pumps delivered verapamil at 3.6 mg/kg/day for 24 (RNA)-48 (protein) hours. After treatment animals were anesthetized and weighed. Hearts were excised, rinsed, blotted dry, weighed, and then frozen on dry ice and the stored at -80oC until studied. Animals were anesthetized and euthanized according to animal protocols approved by the University of Kentucky Institutional Animal Care and Use Committee. This investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication NO. 85-23, revised 1996). Left ventricular free wall from female mice was rapidly excised and either snap frozen at -80oC or used immediately for RNA isolation. Three VER treated mice and 3 vehicle treated mice were used to generate RNA for microarray. Total RNA was isolated using the RNAqueous -4PCR kit (Ambion) and quantitated spectrophotometrically at 260nm. Contaminating genomic DNA was eliminated by DNase treatment (Ambion). RNA quality was assessed using the Agilent 2100 Bioanalyzer. Microarray data was obtained using the Affymetrix 430 V2 GeneChip (representing 45,101 probe sets), in accordance with the manufacturer’s specifications.
2009-12-31 | E-GEOD-8367 | biostudies-arrayexpress
Project description:Using whole-cell patch clamp recording and unbiased gene expression profiling in rat dissociated hippocampal neurons cultured at high density, we demonstrate here that chronic activity blockade induced by the sodium channel blocker tetrodotoxin leads to a homeostatic increase in action potential firing and down-regulation of potassium channel genes. In addition, chronic activity blockade reduces total potassium current, as well as protein expression and current of voltage-gated Kv1 and Kv7 potassium channels, which are critical regulators of action potential firing. Importantly, inhibition of N-Methyl-D-Aspartate receptors alone mimics the effects of tetrodotoxin, including the elevation in firing frequency and reduction of potassium channel gene expression and current driven by activity blockade, whereas inhibition of L-type voltage-gated calcium channels has no effect.
2017-09-21 | GSE104052 | GEO
Project description:Prognosis after myocardial infarction (MI) varies greatly depending of the extent of damaged area and the management of biological processes during recovery. Reportedly, the inhibition of the pro-inflammatory S100A9 reduces myocardial damage after MI. We hypothesize that S100A9 blockade induces changes of major signaling pathways implicated in post-MI healing. The S100A9 blocker (ABR-23890) was given for 3 days after coronary ligation. At 3- and 7-days post-MI, ventricle samples were analyzed versus control and sham-operated mice. Blockade of S100A9 modulated the expressed proteins involved in five biological processes: leu-kocyte cell-cell adhesion, regulation of muscle cell apoptotic process, regulation of intrinsic apoptotic signaling pathway, sarcomere organization and cardiac muscle hypertrophy. The blocker induced regulation of 36 proteins interacting with or targeted by the cellular tumor antigen p53, prevented myocardial compensatory hypertrophy, and reduced cardiac markers of post-ischemic stress. The blockade effect was prominent at day 7 post-MI when the quantitative features of ventricle proteome were closer to controls.
2022-05-19 | PXD033683 | Pride
Project description:Vesicular traffic and membrane contact sites between organelles enable the exchange of proteins, lipids, and metabolites. Recruitment of membrane tethers to contact sites between the endoplasmic reticulum (ER) and the plasma membrane is often triggered by calcium. In contrast, we reveal here a function for calcium in the repression of cholesterol export at membrane contact sites between the ER and the Golgi complex. We show that calcium efflux from ER stores induced by inositol-triphosphate [IP3] accumulation upon loss of the inositol 5-phosphatase INPP5A or sustained receptor signaling triggers the depletion of cholesterol and associated complex glycosphingolipids from the cell surface, resulting in a blockade of clathrin-independent endocytosis (CIE) of bacterial Shiga toxin. This phenotype is caused by the calcium-induced dissociation of oxysterol binding protein (OSBP) from the Golgi complex and from VAP-containing membrane contact sites. Our findings reveal a crucial function for INPP5A-mediated IP3 hydrolysis in the control of lipid exchange at membrane contact sites.
2021-05-06 | MTBLS2444 | MetaboLights
Project description:This project contains a reusable, reproducible, understandable, and extensible reimplementation of the one-dimensional model of the rabbit atrioventricular node by Inada et al. (Inada2009) in the language Modelica.
The Inada model was the first detailed electrophysiological model of the atrioventricular node. It consists of 10 ion channels (background channel I_b, L-type calcium channel I_Ca,L, rapid delayed rectifier channel I_K,r, inward rectifier channel I_K,1, sodium channel I_Na, transient outward channel I_to, hyperpolarization-activated channel I_f, sustained outward channel I_st), two ion pumps (sodium calcium exchanger I_NaCa, sodium potassium pump I_p/I_NaK), and four compartments containing variable Ca2+ concentrations (cytoplasm [Ca 2+ ]_i, junctional sarcoplasmic reticulum [Ca2+]_jsr, network sarcoplasmic reticulum [Ca2+]_nsr, “fuzzy” subspace [Ca ]_sub - which is the “functionally restricted
intracellular space accessible to the Na + /Ca 2+ exchanger as well as to the
L-type Ca 2+ channel and the Ca 2+ -gated Ca 2+ channel in the SR”).
A current version of this model can be found at https://github.com/CSchoel/inamo .
2021-07-22 | MODEL2102090002 | BioModels
Project description:For screening mouse models for CNS diseases for changes in ncRNA expression, we first investigated two models with impaired voltage-gated Ca2+ channel activity, i.e. the lethargic mutant of the auxiliary calcium channel β4 subunit (Cacnb4lh; (Burgess et al. 1997)) and knockout mice for the L-type calcium channel CaV1.3 (Platzer et al. 2000), which have been implicated in a variety of neurological disorders such as psychiatric disorders (Cacnb4) or Parkinsons disease (Cav1.3).
2014-10-31 | E-MTAB-2742 | biostudies-arrayexpress
Project description:For screening mouse models for CNS diseases for changes in ncRNA expression, we first investigated two models with impaired voltage-gated Ca2+ channel activity, i.e. the lethargic mutant of the auxiliary calcium channel β4 subunit (Cacnb4lh; (Burgess et al. 1997)) and knockout mice for the L-type calcium channel CaV1.3 (Platzer et al. 2000), which have been implicated in a variety of neurological disorders such as psychiatric disorders (Cacnb4) or Parkinson’s disease (Cav1.3).
2014-10-31 | E-MTAB-2750 | biostudies-arrayexpress
Project description:Various renal abnormalities including hydronephrosis, polycystic and hydroureter had been reported and these symptoms are present in DiGeorge syndrome, polycystic kidney disease, renal dysplasia and acute kidney failure. However, major target genes of renal abnormalities are not elucidated yet. Previous studies have reported that abnormal calcium homeostasis causes renal disease and calcium homeostasis is regulated by calcium channel. In this study, we focus on Ahnak that regulates calcium homeostasis. Ahnak is expressed in intra-cellular locations such as plasma membrane and cytoplasm. Ahnak plays a role in diverse processes as blood-brain barrier formation, cell structure, migration, calcium channel regulation, and tumor metastasis. Ahnak localization was confirmed in developing mouse kidney and ureter. Imbalance of calcium homeostasis and hydronephrosis which is expanded renal pelvis and hydroureter were observed in Ahnak KO mouse. Moreover, peristalsis movement of smooth muscle in ureter has reduced in Ahnak KO. These results indicated that Ahnak plays pivotal roles in kidney and ureter development and maintaining the function of urinary system. Examination of the gene expression between WT, Ahnak hetero and Ahnak KO kidney and ureter at PN1.
2022-12-05 | GSE218925 | GEO
Project description:This study addresses the individual and combined effects of HIV-1 and methamphetamine (N-methyl-1-phenylpropan-2-amine, METH) on cardiac dysfunction in a transgenic mouse model of HIV/AIDS. METH is abused epidemically and is frequently associated with acquisition of HIV-1 infection or AIDS. We employed microarrays to identify mRNA differences in cardiac left ventricle (LV) gene expression following METH administration (10d, 3mg/kg/d, subcutaneously) in C57Bl/6 wild-type littermates (WT) and Tat-expressing transgenic (TG) mice. Arrays identified 880 differentially expressed genes (expression fold change>1.5, p<0.05) following METH exposure, Tat expression, or both. Using pathway enrichment analysis, mRNAs encoding polypeptides for calcium signaling and contractility were altered in the LV samples. Correlative DNA methylation analysis revealed significant LV DNA methylation changes following METH exposure and Tat expression. By combining these data sets, 38 gene promoters (27 related to METH, 11 related to Tat) exhibited differences by both methods of analysis. Among those, only the promoter for CACNA1C that encodes L-type calcium channel Cav1.2 displayed DNA methylation changes concordant with its gene expression change. Quantitative PCR verified that Cav1.2 LV mRNA abundance doubled following METH. Correlative immunoblots specific for Cav1.2 revealed a 3.5-fold increase in protein abundance in METH LVs. Data implicate Cav1.2 in calcium dysregulation and hypercontractility in the murine LV exposed to METH. They suggest a pathogenetic role for METH exposure to promote LV dysfunction that outweighs Tat-induced effects. This study addresses how HIV-1 and methamphetamine comorbidities affect cardiac (left ventricle) gene expression and epigenetic nuclear DNA methylation.
2016-05-23 | GSE64158 | GEO