The Roles of Rasd1 small G proteins and leptin in the activation of TRPC4 transient receptor potential channels

Wie, Jinhong; Kim, Byung Joo; Myeong, Jongyun; Ha, Kotdaji; Jeong, Seung Joo; Yang, Dongki; Kim, Euiyong; Jeon, Ju Hong; So, Insuk

doi:10.1080/19336950.2015.1058454

Cited by 5 publications

(2 citation statements)

References 87 publications

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“…RASD1 is a monomeric protein expressed at low concentrations in cardiac tissue. 56 Notably, the level of RASD1 was significantly downregulated in volume-overloaded atria, and RASD1 knockdown in atrium-derived cells led to a substantial increase in atrial natriuretic factor expression. 57 , 58 In the present work, we found that RASD1 was decreased in HCM.…”

Section: Discussionmentioning

confidence: 93%

Prediction of diagnostic gene biomarkers for hypertrophic cardiomyopathy by integrated machine learning

You,

Dong

2023

J Int Med Res

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Objectives Hypertrophic cardiomyopathy (HCM), a leading cause of heart failure and sudden death, requires early diagnosis and treatment. This study investigated the underlying pathogenesis and explored potential diagnostic gene biomarkers for HCM. Methods Transcriptional profiles of myocardial tissues from patients with HCM (dataset GSE36961) were downloaded from the Gene Expression Omnibus database and subjected to bioinformatics analyses, including differentially expressed gene (DEG) identification, enrichment analyses, and protein–protein interaction (PPI) network analysis. Least absolute shrinkage and selection operator (LASSO) regression and support vector machine recursive feature elimination were performed to identify candidate diagnostic gene biomarkers. mRNA expression levels of candidate biomarkers were tested in an external dataset (GSE141910); area under the receiver operating characteristic curve (AUC) values were obtained to validate diagnostic efficacy. Results Overall, 156 DEGs (109 downregulated, 47 upregulated) were identified. Enrichment and PPI network analyses indicated that the DEGs were involved in biological functions and molecular pathways including inflammatory response, platelet activity, complement and coagulation cascades, extracellular matrix organization, phagosome, apoptosis, and VEGFA–VEGFR2 signaling. RASD1, CDC42EP4, MYH6, and FCN3 were identified as diagnostic biomarkers for HCM. Conclusions RASD1, CDC42EP4, MYH6, and FCN3 might be diagnostic gene biomarkers for HCM and can provide insights concerning HCM pathogenesis.

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Section: Discussionmentioning

confidence: 93%

Prediction of diagnostic gene biomarkers for hypertrophic cardiomyopathy by integrated machine learning

You,

Dong

2023

J Int Med Res

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“…Rasd1 belongs to the Ras superfamily of small GTPase, which is expressed in the brain, heart, liver, kidney, pancreas, skeletal muscle, and placenta ( Tu and Wu, 1999 ; Bernal and Crespo, 2006 ; Bernal et al, 2021 ). Activation of Gα i subunits by Rasd1 is known to be the primary mechanism for activating TRPC4 ( Wie et al, 2015 ). Another small G protein that may be a novel target for TRPC5, Rac1, is known to mediate podocyte injury in focal segmental glomerulosclerosis.…”

Section: Two Major Kinds Of G Protein: Small G Protein and Heterotrim...mentioning

confidence: 99%

Direct modulation of TRPC ion channels by Gα proteins

Kang,

Kim,

Park

et al. 2024

Front. Physiol.

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GPCR-Gi protein pathways are involved in the regulation of vagus muscarinic pathway under physiological conditions and are closely associated with the regulation of internal visceral organs. The muscarinic receptor-operated cationic channel is important in GPCR-Gi protein signal transduction as it decreases heart rate and increases GI rhythm frequency. In the SA node of the heart, acetylcholine binds to the M2 receptor and the released Gβγ activates GIRK (I(K,ACh)) channel, inducing a negative chronotropic action. In gastric smooth muscle, there are two muscarinic acetylcholine receptor (mAChR) subtypes, M2 and M3. M2 receptor activates the muscarinic receptor-operated nonselective cationic current (mIcat, NSCC(ACh)) and induces positive chronotropic effect. Meanwhile, M3 receptor induces hydrolysis of PIP2 and releases DAG and IP3. This IP3 increases intracellular Ca2+ and then leads to contraction of GI smooth muscles. The activation of mIcat is inhibited by anti-Gi/o protein antibodies in GI smooth muscle, indicating the involvement of Gαi/o protein in the activation of mIcat. TRPC4 channel is a molecular candidate for mIcat and can be directly activated by constitutively active GαiQL proteins. TRPC4 and TRPC5 belong to the same subfamily and both are activated by Gi/o proteins. Initial studies suggested that the binding sites for G protein exist at the rib helix or the CIRB domain of TRPC4/5 channels. However, recent cryo-EM structure showed that IYY58-60 amino acids at ARD of TRPC5 binds with Gi3 protein. Considering the expression of TRPC4/5 in the brain, the direct G protein activation on TRPC4/5 is important in terms of neurophysiology. TRPC4/5 channels are also suggested as a coincidence detector for Gi and Gq pathway as Gq pathway increases intracellular Ca2+ and the increased Ca2+ facilitates the activation of TRPC4/5 channels. More complicated situation would occur when GIRK, KCNQ2/3 (IM) and TRPC4/5 channels are co-activated by stimulation of muscarinic receptors at the acetylcholine-releasing nerve terminals. This review highlights the effects of GPCR-Gi protein pathway, including dopamine, μ-opioid, serotonin, glutamate, GABA, on various oragns, and it emphasizes the importance of considering TRPC4/5 channels as crucial players in the field of neuroscience.

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Oncolytic Reovirus (pelareorep) Induces Autophagy in KRAS-mutated Colorectal Cancer

Jiffry

Thavornwatanayong

Rao

et al. 2021

Clinical Cancer Research

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Purpose: To explore the effects of pelareorep on autophagy in multiple models of colorectal cancer, including patient-derived peripheral blood mononuclear cells (PBMCs). Experimental Design: HCT116 [KRAS mutant (mut)] and Hke3 [KRAS wild-type (WT)] cells were treated with pelareorep (multiplicity of infection, 5) and harvested at 6 and 9 hours. LC3 A/B expression was determined by immunofluorescence and flow cytometry; five autophagic proteins were analyzed by Western blotting. The expression of 88 autophagy genes was determined by qRT-PCR. Syngeneic mouse models, CT26/Balb-C (KRAS mut) and MC38/C57B6 (KRAS WT), were developed and treated with pelareorep (10 × 106 plaque-forming unit/day) intraperitoneally. Protein and RNA were extracted from harvested tumor tissues. PBMCs from five experimental and three control patients were sampled at 0 (pre) and 48 hours, and on days 8 and 15. The gene expression normalized to “pre” was determined using 2−ΔΔCt method. Results: Pelareorep induced significant upregulation of LC3 A/B in HCT116 as compared with Hke3 cells by immunofluorescence (3.24 × and 8.67 ×), flow cytometry (2.37 × and 2.58 ×), and autophagosome formation (2.02 × and 1.57 ×), at 6 and 9 hours, respectively; all P < 0.05. Western blot analysis showed an increase in LC3 A/B (2.38 × and 6.82 ×) and Beclin1 (1.17 × and 1.24 ×) at 6 and 9 hours, ATG5 (2.4 ×) and P-62 (1.52 ×) at 6 hours, and VPS-34 (1.39 ×) at 9 hours (all P < 0.05). Induction of 13 transcripts in cell lines (>4 ×; 6 and 9 hours; P < 0.05), 12 transcripts in CT26 (qRT-PCR), and 14 transcripts in human PBMCs (P < 0.05) was observed. LC3 A/B, RICTOR, and RASD1 expression was upregulated in all three model systems. Conclusions: Pelareorep hijacks host autophagic machinery in KRAS-mut conditions to augment its propagation and preferential oncolysis of the cancer cells.

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The Roles of Rasd1 small G proteins and leptin in the activation of TRPC4 transient receptor potential channels

Cited by 5 publications

References 87 publications

Prediction of diagnostic gene biomarkers for hypertrophic cardiomyopathy by integrated machine learning

Prediction of diagnostic gene biomarkers for hypertrophic cardiomyopathy by integrated machine learning

Direct modulation of TRPC ion channels by Gα proteins

Oncolytic Reovirus (pelareorep) Induces Autophagy in KRAS-mutated Colorectal Cancer

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