A CRITICAL ROLE OF TRPC1-ORAI1-STIM1 MEDIATED STORE OPERATED CALCIUM ENTRY IN CARDIAC HYPERTROPHY

Acute transitions in cytosolic calcium ([Ca2+]i) through store-operated calcium entry channels catalyze interendothelial cell gap formation that increases permeability. However, the rise in [Ca2+]i only disrupts barrier function in the absence of a rise in cAMP. Discovery that type 6 adenylyl cyclase (AC6; EC 4.6.6.1) is inhibited by calcium entry through store-operated calcium entry pathways provided a plausible explanation for how inflammatory [Ca2+]i mediators may decrease cAMP necessary for endothelial cell gap formation. [Ca2+]i mediators only modestly decrease global cAMP concentrations and thus, to date, the physiological role of AC6 is unresolved. Present studies used an adenoviral construct that expresses the calcium-stimulated AC8 to convert normal calcium inhibition into stimulation of cAMP, within physiologically relevant concentration ranges. Thrombin stimulated a dose-dependent [Ca2+]i rise in both pulmonary artery (PAECs) and microvascular (PMVEC) endothelial cells, and promoted intercellular gap formation in both cell types. In PAECs, gap formation was progressive over 2 h, whereas in PMVECs, gap formation was rapid (within 10 min) and gaps resealed within 2 h. Expression of AC8 resulted in a modest calcium stimulation of cAMP, which virtually abolished thrombin-induced gap formation in PMVECs. Findings provide the first direct evidence that calcium inhibition of AC6 is essential for endothelial gap formation.

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On the Role of Store-Operated Calcium Entry in Acute and Chronic Neurodegenerative Diseases

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2018.00087 ◽

2018 ◽

Vol 11 ◽

Cited By ~ 32

Author(s):

Agnese Secondo ◽

Giacinto Bagetta ◽

Diana Amantea

Keyword(s):

Neurodegenerative Diseases ◽

Calcium Entry ◽

Store Operated Calcium Entry

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Cocaine inhibits store-operated Ca2+ entry in brain microvascular endothelial cells: critical role for sigma-1 receptors

Biochemical Journal ◽

10.1042/bj20150934 ◽

2015 ◽

Vol 473 (1) ◽

pp. 1-5 ◽

Cited By ~ 28

Author(s):

G. Cristina Brailoiu ◽

Elena Deliu ◽

Linda M. Console-Bram ◽

Jonathan Soboloff ◽

Mary E. Abood ◽

...

Keyword(s):

Endothelial Cells ◽

Rat Brain ◽

Critical Role ◽

Calcium Entry ◽

Microvascular Endothelial Cells ◽

Brain Microvascular Endothelial Cells ◽

Sigma 1 Receptor ◽

Store Operated Calcium Entry ◽

Sigma 1 ◽

Microvascular Endothelial

We provide evidence that cocaine induces sigma-1 receptor-mediated inhibition of store-operated calcium entry (SOCE) in rat brain microvascular endothelial cells. Thus, we reveal sigma-1 receptors as SOCE blockers, adding novel insight regarding endothelial effects of cocaine and endogenous SOCE modulation.

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Metabolic reprogramming via PPARα signaling in cardiac hypertrophy and failure: From metabolomics to epigenetics

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00103.2017 ◽

2017 ◽

Vol 313 (3) ◽

pp. H584-H596 ◽

Cited By ~ 20

Author(s):

Junco Shibayama Warren ◽

Shin-ichi Oka ◽

Daniela Zablocki ◽

Junichi Sadoshima

Keyword(s):

Cardiac Hypertrophy ◽

Current Knowledge ◽

Critical Role ◽

Cardiac Metabolism ◽

Metabolic Reprogramming ◽

Metabolic Phenotype ◽

Global Changes ◽

Peroxisome Proliferator ◽

Metabolic Remodeling

Studies using omics-based approaches have advanced our knowledge of metabolic remodeling in cardiac hypertrophy and failure. Metabolomic analysis of the failing heart has revealed global changes in mitochondrial substrate metabolism. Peroxisome proliferator-activated receptor-α (PPARα) plays a critical role in synergistic regulation of cardiac metabolism through transcriptional control. Metabolic reprogramming via PPARα signaling in heart failure ultimately propagates into myocardial energetics. However, emerging evidence suggests that the expression level of PPARα per se does not always explain the energetic state in the heart. The transcriptional activities of PPARα are dynamic, yet highly coordinated. An additional level of complexity in the PPARα regulatory mechanism arises from its ability to interact with various partners, which ultimately determines the metabolic phenotype of the diseased heart. This review summarizes our current knowledge of the PPARα regulatory mechanisms in cardiac metabolism and the possible role of PPARα in epigenetic modifications in the diseased heart. In addition, we discuss how metabolomics can contribute to a better understanding of the role of PPARα in the progression of cardiac hypertrophy and failure.

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The Knockout for G Protein-Coupled Receptor-Like PfSR25 Increases the Susceptibility of Malaria Parasites to the Antimalarials Lumefantrine and Piperaquine but Not to Medicine for Malaria Venture Compounds

Frontiers in Microbiology ◽

10.3389/fmicb.2021.638869 ◽

2021 ◽

Vol 12 ◽

Author(s):

Benedito M. Santos ◽

Bárbara K. M. Dias ◽

Myna Nakabashi ◽

Celia R. S. Garcia

Keyword(s):

G Protein ◽

Calcium Entry ◽

G Protein Coupled Receptor ◽

Intracellular Calcium Signaling ◽

Store Operated Calcium Entry ◽

G Protein Coupled ◽

Internal Calcium ◽

Shed Light ◽

Antimalarial Compounds

Previously we have reported that the G protein-coupled receptor (GPCR)-like PfSR25 in Plasmodium falciparum is a potassium (K+) sensor linked to intracellular calcium signaling and that knockout parasites (PfSR25-) are more susceptible to oxidative stress and antimalarial compounds. Here, we explore the potential role of PfSR25 in susceptibility to the antimalarial compounds atovaquone, chloroquine, dihydroartemisinin, lumefantrine, mefloquine, piperaquine, primaquine, and pyrimethamine and the Medicine for Malaria Venture (MMV) compounds previously described to act on egress/invasion (MMV006429, MMV396715, MMV019127, MMV665874, MMV665878, MMV665785, and MMV66583) through comparative assays with PfSR25- and 3D7 parasite strains, using flow cytometry assays. The IC50 and IC90 results show that lumefantrine and piperaquine have greater activity on the PfSR25- parasite strain when compared to 3D7. For MMV compounds, we found no differences between the strains except for the compound MMV665831, which we used to investigate the store-operated calcium entry (SOCE) mechanism. The results suggest that PfSR25 may be involved in the mechanism of action of the antimalarials lumefantrine and piperaquine. Our data clearly show that MMV665831 does not affect calcium entry in parasites after we depleted their internal calcium pools with thapsigargin. The results demonstrated here shed light on new possibilities on the antimalarial mechanism, bringing evidence of the involvement of the GPCR-like PfSR25.

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