STIMs and Orai1 regulate cytokine production in spinal astrocytes

Gao, Xinghua; Xia, Jingsheng; Muñoz, Frances M.; Manners, Melissa T.; Rong, Pan; Meucci, Olimpia; Dai, Yue; Hu, Huijuan

doi:10.1186/s12974-016-0594-7

Cited by 43 publications

(50 citation statements)

References 49 publications

(54 reference statements)

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“…We and others have shown that YM-58483, a SOC inhibitor, attenuates acute, and chronic pain ( Gao et al, 2013 ; Qi et al, 2016 ). Our previous studies have also demonstrated that SOCs are expressed and functional in spinal cord dorsal horn neurons and astrocytes ( Xia et al, 2014 ; Gao et al, 2016 ). To better understand how SOCs are involved in the pain process, we examined the SOC family expression in DRGs.…”

Section: Resultsmentioning

confidence: 91%

“…These findings suggest that SOCs play both central and peripheral roles in chronic pain. Although characteristics of SOCs have been established in spinal cord neurons and astrocytes ( Xia et al, 2014 ; Gao et al, 2016 ), the molecular components of SOCs that mediate SOC entry (SOCE) in dorsal root ganglion (DRG) neurons remain elusive. While a previous study has suggested that Orai1 may be involved in SOCE in DRG neurons ( Gemes et al, 2011 ), a recent report has indicated that TRPC3 also contributes to SOCE in DRG neurons ( Alkhani et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

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Orai1 and Orai3 Mediate Store-Operated Calcium Entry Contributing to Neuronal Excitability in Dorsal Root Ganglion Neurons

Wei

Mei

Xia

et al. 2017

Front. Cell. Neurosci.

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Store-operated calcium channels (SOCs) are highly calcium-selective channels that mediate calcium entry in various cell types. We have previously reported that intraplantar injection of YM-58483 (a SOC inhibitor) attenuates chronic pain. A previous study has reported that the function of SOCs in dorsal root ganglia (DRG) is enhanced after nerve injury, suggesting that SOCs may play a peripheral role in chronic pain. However, the expression, functional distribution and significance of the SOC family in DRG neurons remain elusive and the key components that mediate SOC entry (SOCE) are still controversial. Here, we demonstrated that the SOC family (STIM1, STIM2, Orai1, Orai2, and Orai3) was expressed in DRGs and STIM1 was mainly present in small- and medium-sized DRG neurons. Using confocal live cell imaging, Ca2+ imaging and electrophysiology techniques, we demonstrated that depletion of the endoplasmic reticulum Ca2+ stores induced STIM1 and STIM2 translocation, and that inhibition of STIM1 or blockage of Orai channels with pharmacological tools attenuated SOCE and SOC currents. Using the small inhibitory RNA knockdown approach, we identified STIM1, STIM2, Orai1, and Orai3 as the key components of SOCs mediating SOCE in DRG neurons. Importantly, activation of SOCs by thapsigargin induced plasma membrane depolarization and increased neuronal excitability, which were completely abolished by inhibition of SOCs or double knockdown of Orai1 and Orai3. Our findings suggest that SOCs exert an excitatory action in DRG neurons and provide a potential peripheral mechanism for modulation of pain hypersensitivity by SOC inhibition.

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Section: Resultsmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Orai1 and Orai3 Mediate Store-Operated Calcium Entry Contributing to Neuronal Excitability in Dorsal Root Ganglion Neurons

Wei

Mei

Xia

et al. 2017

Front. Cell. Neurosci.

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“…Primary mouse astrocytes were prepared as previously described [ 47 ] with minimal modification. Briefly, the spinal cord was isolated from neonatal (P1–P2) mice.…”

Section: Methodsmentioning

confidence: 99%

Levo-Corydalmine Alleviates Neuropathic Cancer Pain Induced by Tumor Compression via the CCL2/CCR2 Pathway

Kodithuwakku

Zhou

et al. 2017

Molecules

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Background: Tumor compression-induced pain (TCIP) is a complex pathological cancer pain. Spinal glial cells play a critical role in maintenance of cancer pain by releasing proinflammatory cytokines and chemokines. In this study, we verified the role of levo-corydalmine (l-CDL) on TCIP. Methods: Spontaneous pain, paw withdrawal threshold and latency were assessed using TCIP mouse model. Immunofluorescence was used to identify the reactions of glia. RT-PCR and western blot or ELISA were used to determine mRNA or protein expression of tumor necrosis factor-α (TNF-α), interlukin-1β (IL-1β), CC chemokine ligand 2 (CCL2) and chemotactic cytokine receptor 2 (CCR2) in vivo and in vitro. Results: l-CDL significantly attenuated TCIP hypersensitivity, accompanying with downregulation of TNF-α and IL-1β expression levels and declined astrocytes and microglial activation. It also significantly decreased the expression of the mRNA and protein level for CCL2 and CCR2. Further, l-CDL could suppress TNF-α-induced astrocytes activation and IL-1β expression through downregulating the CCL2/CCR2. Besides, CCL2-induced BV-microglia activation and inflammatory factors secretion were suppressed by l-CDL via CCR2. Conclusions: Suppression of CCL2/CCR2 by l-CDL may contribute to alleviate TCIP, offering an alternative medication for TCIP.

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“…Furthermore, a recent study has revealed in spinal cord astrocytes that STIM2 participates in lipopolysaccharide (LPS)‐induced cytokine production (Gao et al . ). STIM2 knockdown significantly reduces SOCE and LPS‐induced interleukin (IL)‐6 and tumour necrosis factor α (TNF‐α) production, cytokines that are involved and upregulated in pain hypersensitivity (Gao et al .…”

Section: Introductionmentioning

confidence: 97%

“…STIM2 knockdown significantly reduces SOCE and LPS‐induced interleukin (IL)‐6 and tumour necrosis factor α (TNF‐α) production, cytokines that are involved and upregulated in pain hypersensitivity (Gao et al . ).…”

Section: Introductionmentioning

confidence: 97%

Role of STIM2 in cell function and physiopathology

Berna‐Erro

Jardín

Salido

et al. 2017

The Journal of Physiology

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An endoplasmic reticulum (ER)-resident protein that regulates cytosolic and ER free-Ca concentration by induction of store-operated calcium entry: that is the original definition of STIM2 and its function. While its activity strongly depends on the amount of calcium stored in the ER, its function goes further, to intracellular signalling and gene expression. Initially under-studied owing to the prominent function of STIM1, STIM2 came to be regarded as vital in mice, gradually emerging as an important player in the nervous system, and cooperating with STIM1 in the immune system. STIM2 has also been proposed as a relevant player in pathological conditions related to ageing, Alzheimer's and Huntington's diseases, autoimmune disorders and cancer. The discovery of additional functions, together with new splicing forms with opposite roles, has clarified existing controversies about STIM2 function in SOCE. With STIM2 being essential for life, but apparently not for development, newly available data demonstrate a complex and still intriguing behaviour that this review summarizes, updating current knowledge of STIM2 function.

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STIMs and Orai1 regulate cytokine production in spinal astrocytes

Cited by 43 publications

References 49 publications

Orai1 and Orai3 Mediate Store-Operated Calcium Entry Contributing to Neuronal Excitability in Dorsal Root Ganglion Neurons

Orai1 and Orai3 Mediate Store-Operated Calcium Entry Contributing to Neuronal Excitability in Dorsal Root Ganglion Neurons

Levo-Corydalmine Alleviates Neuropathic Cancer Pain Induced by Tumor Compression via the CCL2/CCR2 Pathway

Role of STIM2 in cell function and physiopathology

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