CACNB2 is associated with aberrant RAS-MAPK signaling in hypertensive Dahl Salt-Sensitive rats

Pandian, Vishnuprabu Durairaj; Giovannucci, David R.; Vázquez, Guillermo; Kumarasamy, Sivarajan

doi:10.1016/j.bbrc.2019.03.215

Cited by 7 publications

(5 citation statements)

References 27 publications

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“…Our results show that the gene coding for the adrenergic α1 receptor ( ADRA1A ) was upregulated in BD, along with the downstream thermogenesis pathway genes ( SMARCD3, ADCY2, ARID1A, ADCY8, PRKG1, MAP3K5, SMARCA4, FGFR1 ) 74 . However, genes implicated in the mobilisation and the increase of calcium and calcium signalling were downregulated ( PPP3CA, GNA14, PPP3CC, STIM2, ITPR2, PLCG1, CALM2, SLC8A1 ), including the GWAS gene CACNB2 , which also codes for a subunit of a voltage-gated calcium channel 39 . In parallel, we found an upregulation of cAMP producing enzymes ADCY2 and ADCY8, with a downregulation of UGP2, which contributes to glycogen synthesis.…”

Section: Resultsmentioning

confidence: 99%

“…Of those genes, 43 are expressed by at least 5% of astrocytes or microglia in our study (Figure 3A). We then used MAST 34 to perform a differential gene expression (DGE) analysis using a mixed effects model, between BD and CT samples and found that several of the GWAS genes were differentially expressed in glial cells (padj < 0.1, |logFC| > 0.1; Figure 3B, C): in astrocytes ADCY2 (padj= 0.092, logFC =0.698) coding for an isoform of adenylyl cyclase that catalyses the formation of cyclic adenosine monophosphate (cAMP) from ATP and is involved in cAMP-PKA signalling, regulating multiple cellular functions such as glycogen metabolism [35][36][37][38] ; CACNB2 (padj= 0.0669, logFC = -2.607), a subunit of a voltage-gated calcium channels which has been associated with hypertension 39,40 and brain cognitive dysfunctions in BD 41,42 ; NCAN (padj= 0.015, logFC = 0.785), a component of brain ECM and specifically of brain perineuronal nets that regulate synaptic structure and function [43][44][45][46][47] , which also contributes to the formation of glial scar in response to injury [48][49][50] ; SLC25A17 (padj= 0.0369, logFC = 0.268), a peroxisomal transporter 51 ; and FSTL5 (padj= 0.007, logFC = -0.352), coding for a Wnt signalling-associated protein 52 shown to be implicated in caspase-dependent apoptosis 53 (Figure 3B). In microglia, 3 genes were significantly altered: SSBP2 (padj= 0.00018, logFC = 0.754), a highly ubiquitously expressed gene coding for a single-stranded DNA binding protein 54 ; STK4 (padj= 0.0231, logFC = -0.15), which is involved in microglial apoptosis and may contribute to microglial activation 55,56 ; and CD47 (padj= 0.0856, logFC = -0.199), which codes for an inhibitor of microglial phagocytosis contributing to the regulation of synaptic pruning during development 57,58 (Figure 3C).…”

Section: Bd Risk Factor Genes Are Differentially Expressed In Astrocy...mentioning

confidence: 99%

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Altered astrocytic and microglial homeostasis characterizes a decreased proinflammatory state in bipolar disorder

Amossé,

Tournier,

Badina

et al. 2023

Preprint

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Multiple lines of evidence point to peripheral immune alterations in bipolar disorder (BD) although the activity of brain immune mechanisms remain largely unexplored. To identify the cell type-specific immune alterations in the BD brain, we performed a proteomic and single nuclear transcriptomic analysis ofpostmortemcingulate cortex samples from BD and control subjects. Our results showed that genes associated to the genetic risk for BD are enriched in microglia and astrocytes. Transcriptomic alterations in microglia point to a reduced proinflammatory phenotype, associated to reduced resistance to oxidative stress and apoptosis, which was confirmed with immunohistochemical quantification of IBA1 density. Astrocytes show transcriptomic evidence of an imbalance of multiple metabolic pathways, extracellular matrix composition and downregulated immune signalling. These alterations are associated toADCY2andNCAN,two GWAS genes upregulated in astrocytes. Finally, cell-cell communication analysis prioritized upregulated SPP1-CD44 signalling to astrocytes as a potential regulator of the transcriptomic alterations in BD. Our results indicate that microglia and astrocytes are characterized by downregulated immune responses associated to a dysfunction of core mechanisms via which these cells contribute to brain homeostasis.

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Section: Resultsmentioning

confidence: 99%

Section: Bd Risk Factor Genes Are Differentially Expressed In Astrocy...mentioning

confidence: 99%

Altered astrocytic and microglial homeostasis characterizes a decreased proinflammatory state in bipolar disorder

Amossé,

Tournier,

Badina

et al. 2023

Preprint

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“…HLA-DOB, PSMB8, and TAP1 were involved in immune, protein and fat metabolism processes ( Nagarajan et al, 2002 ; Niesporek et al, 2005 ; Garg, 2011 ; Kolbus et al, 2012 ; Arimochi et al, 2016 ; Naderi et al, 2016 ; Moussa et al, 2018 ; Yang et al, 2018 ; Chen et al, 2020 ). CACNB2 was involved in the regulation of ion membrane transport, which was related to calcium channel activity, MAPK, and oxytocin signaling pathways ( Durairaj Pandian et al, 2019 ), and studies have shown that CACNB2 was involved in the formation of porcine marlin ( Bertolini et al, 2018 ). NSUN6 protein might have an important function in broad aspects of embryonic development ( Chi and Delgado-Olguín, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of SNPs and Candidate Genes for Milk Production Ability in Yorkshire Pigs

et al. 2021

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Sow milk production ability is an important limiting factor impacting suboptimal growth and the survival of piglets. Through pig genetic improvement, litter sizes have been increased. Larger litters need more suckling mammary glands, which results in increased milk from the lactating sow. Hence, there is much significance to exploring sow lactation performance. For milk production ability, it is not practical to directly measure the milk yield, we used litter weight gain (LWG) throughout sow lactation as an indicator. In this study, we estimated the heritability of LWG, namely, 0.18 ± 0.07. We then performed a GWAS, and detected seven significant SNPs, namely, Sus scrofa Chromosome (SSC) 2: ASGA0010040 (p = 7.73E-11); SSC2:MARC0029355 (p = 1.30E-08), SSC6: WU_10.2_6_65751151 (p = 1.32E-10), SSC7: MARC0058875 (p = 4.99E-09), SSC10: WU_10.2_10_49571394 (p = 6.79E-08), SSC11: M1GA0014659 (p = 1.19E-07), and SSC15: MARC0042106 (p = 1.16E-07). We performed the distribution of phenotypes corresponding to the genotypes of seven significant SNPs and showed that ASGA0010040, MARC0029355, MARC0058875, WU_10.2_10_49571394, M1GA0014659, and MARC0042106 had extreme phenotypic values that corresponded to the homozygous genotypes, while the intermediate values corresponded to the heterozygous genotypes. We screened for flanking regions ± 200 kb nearby the seven significant SNPs, and identified 38 genes in total. Among them, 28 of the candidates were involved in lactose metabolism, colostrum immunity, milk protein, and milk fat by functional enrichment analysis. Through the combined analysis between 28 candidate genes and transcriptome data of the sow mammary gland, we found nine commons (ANO3, MUC15, DISP3, FBXO6, CLCN6, HLA-DRA, SLA-DRB1, SLA-DQB1, and SLA-DQA1). Furthermore, by comparing the chromosome positions of the candidate genes with the quantitative trait locus (QTLs) as previously reported, a total of 17 genes were found to be within 0.86–94.02 Mb of the reported QTLs for sow milk production ability, in which, NAV2 was found to be located with 0.86 Mb of the QTL region ssc2: 40936355. In conclusion, we identified seven significant SNPs located on SSC2, 6, 7, 10, 11, and 15, and propose 28 candidate genes for the ability to produce milk in Yorkshire pigs, 10 of which were key candidates.

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“…For example, the molecular signals released by the β subunit guide α1 subunit transport to the plasma membrane to construct the correct functional protein complex [30]. In addition, Durairaj Pandian V et al found that the overexpression of CACNB2 can upregulate the gene expression of the RAS-MAPK pathway, which is one of the key chain reactions of hypertension [31].…”

Section: Discussionmentioning

confidence: 99%

Association between gene polymorphisms of voltage-dependent Ca2+ channels and hypertension in the Dai people of China: a case-control study

et al. 2020

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Background: Abnormal calcium homeostasis related to the development of hypertension. As the key regulator of intracellular calcium concentration, voltage-dependent calcium channels (VDCCs), the variations in these genes may have important effects on the development of hypertension. Here we evaluate VDCCs variability with respect to hypertension in the Dai ethnic group of China. Methods: A total of 1034 samples from Dai individuals were collected, of which 495 were used as cases, and 539 were used as controls. Blood pressure was measured using a standard mercury measurement method, three times with a rest for 5 min, and the average was used for analyses. Seventeen single nucleotide polymorphisms (SNPs) in the four protein-coding genes (CACNA1A, CACNA1C, CACNA1S, CACNB2) of VDCCs were identified by multiplex PCR-SNP typing technique. Chi-square tests and regression models were used to analyse the associations of SNPs with hypertension. Results: The results of chi-square tests showed that the allele frequencies of 5 SNPs were significantly different between the case and the control groups (P < 0.05), but the statistical significance was lost after Bonferroni's correction. However, after adjusting for BMI, age, sex and other factors by logistic regression analyses, the results showed that 5 SNPs consistent with chi-square tests (rs2365293, rs17539088, rs16917217, rs61839222 and rs10425859) were still statistically positive. Conclusions: This finding suggested that the significant association of these SNPs with hypertension may be noteworthy in future studies.

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CACNB2 is associated with aberrant RAS-MAPK signaling in hypertensive Dahl Salt-Sensitive rats

Cited by 7 publications

References 27 publications

Altered astrocytic and microglial homeostasis characterizes a decreased proinflammatory state in bipolar disorder

Altered astrocytic and microglial homeostasis characterizes a decreased proinflammatory state in bipolar disorder

Identification of SNPs and Candidate Genes for Milk Production Ability in Yorkshire Pigs

Association between gene polymorphisms of voltage-dependent Ca2+ channels and hypertension in the Dai people of China: a case-control study

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