Modulation of Cerebral Store-operated Calcium Entry-regulatory Factor (SARAF) and Peripheral Orai1 Following Focal Cerebral Ischemia and Preconditioning in Mice

Russa, Daniele La; Frisina, Marialaura; Secondo, Agnese; Bagetta, Giacinto; Amantea, Diana

doi:10.1016/j.neuroscience.2020.06.014

Cited by 17 publications

(12 citation statements)

References 76 publications

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“…Moreover, similar to STIM1 and Orai1, the expression of SARAF has also been shown to be regulated by androgen receptor stimulation [108,111,112]. Although changes in SARAF transcripts or protein levels have been reported in a number of pathologies, including pancreatitis [113], cancer [111,114], and neurodegenerative [114][115][116] or cardiovascular [117][118][119][120][121] diseases, there is no direct indication that loss-or gain-of-function mutations in SARAF lead to any specific pathophysiology at this time.…”

Section: The Physiological Role Of Sarafmentioning

confidence: 99%

Regulation of Store-Operated Ca2+ Entry by SARAF

Dagan

Palty

2021

Cells

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Calcium (Ca2+) signaling plays a dichotomous role in cellular biology, controlling cell survival and proliferation on the one hand and cellular toxicity and cell death on the other. Store-operated Ca2+ entry (SOCE) by CRAC channels represents a major pathway for Ca2+ entry in non-excitable cells. The CRAC channel has two key components, the endoplasmic reticulum Ca2+ sensor stromal interaction molecule (STIM) and the plasma-membrane Ca2+ channel Orai. Physical coupling between STIM and Orai opens the CRAC channel and the resulting Ca2+ flux is regulated by a negative feedback mechanism of slow Ca2+ dependent inactivation (SCDI). The identification of the SOCE-associated regulatory factor (SARAF) and investigations of its role in SCDI have led to new functional and molecular insights into how SOCE is controlled. In this review, we provide an overview of the functional and molecular mechanisms underlying SCDI and discuss how the interaction between SARAF, STIM1, and Orai1 shapes Ca2+ signaling in cells.

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Section: The Physiological Role Of Sarafmentioning

confidence: 99%

Regulation of Store-Operated Ca2+ Entry by SARAF

Dagan

Palty

2021

Cells

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“…SARAF appears to play a negative regulatory role in both STIM1-Orai1-and STIM1-TRPC1-mediated Ca 2+ entry by destabilizing STIM1/Orai1 complexes (Palty et al, 2012). Notably, a recent study reported a reduction of the expression of STIM1 and SARAF in the ischemic cortex, indicating that SARAF may be a new neuroprotective target for the treatment of stroke (La Russa et al, 2020).…”

Section: Sarafmentioning

confidence: 98%

Target Molecules of STIM Proteins in the Central Nervous System

Serwach

Gruszczynska-Biegala

2020

Front. Mol. Neurosci.

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Stromal interaction molecules (STIMs), including STIM1 and STIM2, are single-pass transmembrane proteins that are located predominantly in the endoplasmic reticulum (ER). They serve as calcium ion (Ca2+) sensors within the ER. In the central nervous system (CNS), they are involved mainly in Orai-mediated store-operated Ca2+ entry (SOCE). The key molecular components of the SOCE pathway are well-characterized, but the molecular mechanisms that underlie the regulation of this pathway need further investigation. Numerous intracellular target proteins that are located in the plasma membrane, ER, cytoskeleton, and cytoplasm have been reported to play essential roles in concert with STIMs, such as conformational changes in STIMs, their translocation, the stabilization of their interactions with Orai, and the activation of other channels. The present review focuses on numerous regulators, such as Homer, SOCE-associated regulatory factor (SARAF), septin, synaptopodin, golli proteins, partner of STIM1 (POST), and transcription factors and proteasome inhibitors that regulate STIM-Orai interactions in the CNS. Further we describe novel roles of STIMs in mediating Ca2+ influx via other than Orai pathways, including TRPC channels, VGCCs, AMPA and NMDA receptors, and group I metabotropic glutamate receptors. This review also summarizes recent findings on additional molecular targets of STIM proteins including SERCA, IP3Rs, end-binding proteins (EB), presenilin, and CaMKII. Dysregulation of the SOCE-associated toolkit, including STIMs, contributes to the development of neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, and Huntington's disease), traumatic brain injury, epilepsy, and stroke. Emerging evidence points to the role of STIM proteins and several of their molecular effectors and regulators in neuronal and glial physiology and pathology, suggesting their potential application for future therapeutic strategies.

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“…Interestingly, in a rat model of ischemic stroke, Secondo et al reported that STIM1 and Orai1 proteins were significantly decreased in the ipsilesional cortex. Similarly, STIM1 and Orai1 transcripts and proteins were also reduced after exposure of rat cortical neurons to oxygen and glucose deprivation for 3 h, leading to decreases in SOCE and CRAC currents (Secondo et al, 2019;La Russa et al, 2020). Silencing of STIM1 or Orai1 negated the effect of ischemic preconditioning, which would normally induce increased tolerance for ischemia, and lead to ER stress and increased neuronal death (Secondo et al, 2019), suggesting that Orai1-mediated SOCE is required for ischemic preconditioning.…”

Section: Socs In Acquired Brain Injurymentioning

confidence: 98%

Store-Operated Calcium Channels in Physiological and Pathological States of the Nervous System

Zhang

2020

Front. Cell. Neurosci.

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Store-operated calcium channels (SOCs) are widely expressed in excitatory and non-excitatory cells where they mediate significant store-operated calcium entry (SOCE), an important pathway for calcium signaling throughout the body. While the activity of SOCs has been well studied in non-excitable cells, attention has turned to their role in neurons and glia in recent years. In particular, the role of SOCs in the nervous system has been extensively investigated, with links to their dysregulation found in a wide variety of neurological diseases from Alzheimer’s disease (AD) to pain. In this review, we provide an overview of their molecular components, expression, and physiological role in the nervous system and describe how the dysregulation of those roles could potentially lead to various neurological disorders. Although further studies are still needed to understand how SOCs are activated under physiological conditions and how they are linked to pathological states, growing evidence indicates that SOCs are important players in neurological disorders and could be potential new targets for therapies. While the role of SOCE in the nervous system continues to be multifaceted and controversial, the study of SOCs provides a potentially fruitful avenue into better understanding the nervous system and its pathologies.

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Modulation of Cerebral Store-operated Calcium Entry-regulatory Factor (SARAF) and Peripheral Orai1 Following Focal Cerebral Ischemia and Preconditioning in Mice

Cited by 17 publications

References 76 publications

Regulation of Store-Operated Ca2+ Entry by SARAF

Regulation of Store-Operated Ca2+ Entry by SARAF

Target Molecules of STIM Proteins in the Central Nervous System

Store-Operated Calcium Channels in Physiological and Pathological States of the Nervous System

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