Sigma‐1 receptor activation‐induced glycolytic ATP production and endothelial barrier enhancement

Motawe, Zeinab Y.; Farsaei, Forouzandeh; Abdelmaboud, Salma S.; Cuevas, Javier; Breslin, Jerome W.

doi:10.1111/micc.12620

Cited by 18 publications

(5 citation statements)

References 50 publications

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“…Our data were further substantiated when EC barrier disruption caused by human septic plasma was protected in the presence of PRE-084. These observations are in line with earlier studies in human dermal lymphatic endothelial cells (HDLECs) and human umbilical vein endothelial cells (HUVECs), where Sig1R is shown to be protective against endothelial barrier disruption through its ability to enhance glycolytic energy production [ 52 , 53 ]. Furthermore, since Ca 2+ plays a critical role in intracellular signaling and is a critical mediator of EC permeability, we also tested the ability of Sigma1R to control Ca 2+ signaling in EC.…”

Section: Discussionsupporting

confidence: 89%

The Protective Role of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Protein Sigma-1 Receptor in Regulating Endothelial Inflammation and Permeability Associated with Acute Lung Injury

Mahamed,

Shadab,

Najar

et al. 2023

Cells

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Earlier studies from our lab identified endoplasmic reticulum (ER) chaperone BiP/GRP78, an important component of MAM, to be a novel determinant of endothelial cell (EC) dysfunction associated with acute lung injury (ALI). Sigma1R (Sig1R) is another unique ER receptor chaperone that has been identified to associate with BiP/GRP78 at the MAM and is known to be a pluripotent modulator of cellular homeostasis. However, it is unclear if Sig1R also plays a role in regulating the EC inflammation and permeability associated with ALI. Our data using human pulmonary artery endothelial cells (HPAECs) showed that siRNA-mediated knockdown of Sig1R potentiated LPS-induced the expression of proinflammatory molecules ICAM-1, VCAM-1 and IL-8. Consistent with this, Sig1R agonist, PRE-084, known to activate Sig1R by inducing its dissociation from BiP/GRP78, blunted the above response. Notably, PRE-084 failed to blunt LPS-induced inflammatory responses in Sig1R-depleted cells, confirming that the effect of PRE-084 is driven by Sig1R. Furthermore, Sig1R antagonist, NE-100, known to inactivate Sig1R by blocking its dissociation from BiP/GRP78, failed to block LPS-induced inflammatory responses, establishing that dissociation from BiP/GRP78 is required for Sig1R to exert its anti-inflammatory action. Unlike Sig1R, the siRNA-mediated knockdown or Subtilase AB-mediated inactivation of BiP/GRP78 protected against LPS-induced EC inflammation. Interestingly, the protective effect of BiP/GRP78 knockdown or inactivation was abolished in cells that were depleted of Sig1R, confirming that BiP/GRP78 knockdown/inactivation-mediated suppression of EC inflammation is mediated via Sig1R. In view of these findings, we determined the in vivo relevance of Sig1R in a mouse model of sepsis-induced ALI. The intraperitoneal injection of PRE-084 mitigated sepsis-induced ALI, as evidenced by a decrease in ICAM-1, IL-6 levels, lung PMN infiltration, and lung vascular leakage. Together, these data evidence a protective role of Sig1R against endothelial dysfunction associated with ALI and identify it as a viable target in terms of controlling ALI in sepsis.

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Section: Discussionsupporting

confidence: 89%

The Protective Role of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Protein Sigma-1 Receptor in Regulating Endothelial Inflammation and Permeability Associated with Acute Lung Injury

Mahamed,

Shadab,

Najar

et al. 2023

Cells

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“…Although thought to be specific to the σ1R, a study has shown that it can have some off-target effects. PRE-084 could elicit an enhanced barrier function of human umbilical vein endothelial cell (HUVEC) monolayers in a dose-dependent fashion, and even with significant siRNA knockdown of the σ1R, PRE-084 maintained the barrier function effect, meaning that either only a low occupancy of σ1R is required for the barrier function effect, or that another receptor is involved [ 385 ].…”

Section: Sigma Receptor Ligands For Neurological Diseasementioning

confidence: 99%

Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders

Malar,

Thitilertdecha,

Ruckvongacheep

et al. 2023

CNS Drugs

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The sigma-1 receptor is a 223 amino acid-long protein with a recently identified structure. The sigma-2 receptor is a genetically unrelated protein with a similarly shaped binding pocket and acts to influence cellular activities similar to the sigma-1 receptor. Both proteins are highly expressed in neuronal tissues. As such, they have become targets for treating neurological diseases, including Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), multiple sclerosis (MS), Rett syndrome (RS), developmental and epileptic encephalopathies (DEE), and motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). In recent years, there have been many pre-clinical and clinical studies of sigma receptor (1 and 2) ligands for treating neurological disease. Drugs such as blarcamesine, dextromethorphan and pridopidine, which have sigma-1 receptor activity as part of their pharmacological profile, are effective in treating multiple aspects of several neurological diseases. Furthermore, several sigma-2 receptor ligands are under investigation, including CT1812, rivastigmine and SAS0132. This review aims to provide a current and up-to-date analysis of the current clinical and pre-clinical data of drugs with sigma receptor activities for treating neurological disease.

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“…However, it has also been suggested that Afobazole-induced NO-independent effects, as afobazole treatment in the presence of NOS inhibitor L-NAME led to a decrease in the normalized end-diastolic diameter of the isolated lymphatic vessel ( Trujillo et al, 2017 ). Recently, Sigmar1’s role in lymphatic endothelial barrier function has been demonstrated by a study showing the contribution of Sigmar1 to basal lymphatic endothelial barrier function, potentially through the enhancement of glycolytic energy production in cultured adult human dermal lymphatic endothelial cells ( Motawe et al, 2020 ). Despite all these pharmacologic data collected using non-selective ligands, the molecular role of Sigmar1 in the pathophysiology associated with the lymphatic system remains unknown.…”

Section: Physiological and Pathological Role Of Sigmar1mentioning

confidence: 99%

Sigmar1’s Molecular, Cellular, and Biological Functions in Regulating Cellular Pathophysiology

et al. 2021

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The Sigma 1 receptor (Sigmar1) is a ubiquitously expressed multifunctional inter-organelle signaling chaperone protein playing a diverse role in cellular survival. Recessive mutation in Sigmar1 have been identified as a causative gene for neuronal and neuromuscular disorder. Since the discovery over 40 years ago, Sigmar1 has been shown to contribute to numerous cellular functions, including ion channel regulation, protein quality control, endoplasmic reticulum-mitochondrial communication, lipid metabolism, mitochondrial function, autophagy activation, and involved in cellular survival. Alterations in Sigmar1’s subcellular localization, expression, and signaling has been implicated in the progression of a wide range of diseases, such as neurodegenerative diseases, ischemic brain injury, cardiovascular diseases, diabetic retinopathy, cancer, and drug addiction. The goal of this review is to summarize the current knowledge of Sigmar1 biology focusing the recent discoveries on Sigmar1’s molecular, cellular, pathophysiological, and biological functions.

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Sigma‐1 receptor activation‐induced glycolytic ATP production and endothelial barrier enhancement

Cited by 18 publications

References 50 publications

The Protective Role of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Protein Sigma-1 Receptor in Regulating Endothelial Inflammation and Permeability Associated with Acute Lung Injury

The Protective Role of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Protein Sigma-1 Receptor in Regulating Endothelial Inflammation and Permeability Associated with Acute Lung Injury

Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders

Sigmar1’s Molecular, Cellular, and Biological Functions in Regulating Cellular Pathophysiology

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