Role of STIM2 and Orai proteins in regulating TRPC1 channel activity upon calcium store depletion

Shalygin, Alexey; Kolesnikov, Dmitrii; Glushankova, Liubov; Gusev, Konstantin; Skopin, Anton Yu.; Skobeleva, Ksenia; Kaznacheyeva, Еlena

doi:10.1016/j.ceca.2021.102432

Cited by 14 publications

(8 citation statements)

References 72 publications

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“…We further explored how PLXND1 regulates the concentration of intracellular calcium in EECs. Given that ECs are non-excitable cells, and that calcium channels on the membrane mainly pertain to the ORAI and TRPC protein families ( Shalygin et al, 2021 ), we speculated that the insufficient calcium concentration in EECs results from calcium entry dysfunction through ORAI1. Therefore, we investigated whether PLXND1 may have the ability to change the ORAI1, which could potentially alter its control of calcium signals.…”

Section: Resultsmentioning

confidence: 99%

“…This triggers the action potential, leading to focal ectopic firing. In contrast, EECs serve as non-excited cells, and the ORAI and TRPC families are considered to be the major calcium entry pathways ( Shalygin et al, 2021 ). In the present study, we utilized a calcium fluorescence probe to mark calcium ions in EECs and found that ORAI1-mediated calcium influx was decreased.…”

Section: Discussionmentioning

confidence: 99%

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PLXND1-mediated calcium dyshomeostasis impairs endocardial endothelial autophagy in atrial fibrillation

et al. 2022

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Left atrial appendage (LAA) thrombus detachment resulting in intracranial embolism is a major complication of atrial fibrillation (AF). Endocardial endothelial cell (EEC) injury leads to thrombosis, whereas autophagy protects against EEC dysfunction. However, the role and underlying mechanisms of autophagy in EECs during AF have not been elucidated. In this study, we isolated EECs from AF model mice and observed reduced autophagic flux and intracellular calcium concentrations in EECs from AF mice. In addition, we detected an increased expression of the mechanosensitive protein PLXND1 in the cytomembranes of EECs. PLXND1 served as a scaffold protein to bind with ORAI1 and further decreased ORAI1-mediated calcium influx. The decrease in the calcium influx-mediated phosphorylation of CAMK2 is associated with the inhibition of autophagy, which results in EEC dysfunction in AF. Our study demonstrated that the change in PLXND1 expression contributes to intracellular calcium dyshomeostasis, which inhibits autophagy flux and results in EEC dysfunction in AF. This study provides a potential intervention target for EEC dysfunction to prevent and treat intracardiac thrombosis in AF and its complications.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

PLXND1-mediated calcium dyshomeostasis impairs endocardial endothelial autophagy in atrial fibrillation

et al. 2022

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“…IP 3 then binds with the IP 3 receptor (IP 3 R), opening the Ca 2+ release channel in the ER and facilitating release of Ca 2+ . On sensing the depletion of ER Ca 2+ , STIM1 translocates into the membrane junction between ER and plasma membrane, activating Orai1 channel or transient receptor channel (TRPC), which results in the influx of Ca 2+ [ 17 - 20 ].…”

Section: Stim1/cgas-sting Signal Pathwaymentioning

confidence: 99%

cGAS-STING Pathway Performance in the Vulnerable Atherosclerotic Plaque

Wan¹,

Tian²,

Hao³

et al. 2022

Aging and disease

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The important role of Ca 2+ in pathogenic store-operated calcium entry (SOCE) is well-established. Among the proteins involved in the calcium signaling pathway, Stromal interacting molecule 1 (STIM1) is a critical endoplasmic reticulum transmembrane protein. STIM1 is activated by the depletion of calcium stores and then binds to another calcium protein, Orai1, to form a channel through which the extracellular Ca 2+ can enter the cytoplasm to replenish the calcium store. Multiple studies have shown that increased STIM1 facilitates the aberrant proliferation and apoptosis of vascular smooth cells (VSMC) and macrophages which can promote the formation of rupture-prone plaque. Together with regulating the cytosolic Ca 2+ concentration, STIM1 also activates STING through altered intracellular Ca 2+ concentration, a critical pro-inflammatory molecule. The cGAS-STING pathway is linked with cellular proliferation and phenotypic conversion of VSMC and enhances the progression of atherosclerosis plaque. In summary, we conclude that STIM1/cGAS-STING is involved in the progression of AS and plaque vulnerability.

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“…The main player of SOCE pathway in non-excitable cells are ORAI channels which are regulated by STIM1/2 (STromal Interaction Molecule) proteins. Moreover, a number of articles suggest that sensitivity of TRPC channels to the Ca 2+ store depletion may depend in part on ORAI-mediated Ca 2+ entry [22][23][24][25].…”

Section: Introductionmentioning

confidence: 99%

Reorganization and suppression of store-operated calcium entry in podocytes induced by diabetes type 2

Gusev

Shalygin

Kolesnikov

et al. 2023

Preprint

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Type 2 diabetes mellitus (DM2) is a widespread metabolic disorder that results in podocyte damage and diabetic nephropathy. Previous studies demonstrated that TRPC6 channels play a pivotal role in podocyte function and their dysregulation is associated with development of different kidney diseases including nephropathy. It was assumed that activation of TRPC6 channels leads directly to the Ca2+ influx into cells. Another Ca2+ influx pathway, a store-operated Ca2+ entry (SOCE) via ORAI channels, was also shown to be disturbed during the diabetes development. Here, using single channel patch clamp technique, we demonstrated that non-selective cationic TRPC6 channels are sensitive to the Ca2+ store depletion in human podocyte cell line Ab8/13 and in freshly isolated rat glomerular podocytes. Ca2+ imaging indicated the involvement of ORAI and sodium-calcium exchanger (NCX) in Ca2+ entry induced upon store depletion. Ca2+ inflow by NCX is a result of pronounced TRPC6-mediated Na+ influx leading moreover to the membrane depolarization and ORAI suppression. In rats fed a high-fat diet combined with a low-dose streptozotocin injection, which leads to DM2 development, we observed the reduction of SOCE in rat glomerular podocytes. This was accompanied by a reorganization of store-operated Ca2+ influx such that TRPC6 channels lost their sensitivity to Ca2+ store depletion and ORAI-mediated Ca2+ entry is suppressed in TRPC6-independent manner. Altogether our data provide new insights into the mechanism of SOCE organization in podocytes in the norm and in pathology, which should be taken into account in the pharmacological treatment of the early stages of diabetic nephropathy.

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Role of STIM2 and Orai proteins in regulating TRPC1 channel activity upon calcium store depletion

Cited by 14 publications

References 72 publications

PLXND1-mediated calcium dyshomeostasis impairs endocardial endothelial autophagy in atrial fibrillation

PLXND1-mediated calcium dyshomeostasis impairs endocardial endothelial autophagy in atrial fibrillation

cGAS-STING Pathway Performance in the Vulnerable Atherosclerotic Plaque

Reorganization and suppression of store-operated calcium entry in podocytes induced by diabetes type 2

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