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

Brailoiu, G. Cristina; Deliu, Elena; Console-Bram, Linda; Soboloff, Jonathan; Abood, Mary E.; Unterwald, Ellen M.; Brǎiloiu, Eugen

doi:10.1042/bj20150934

Cited by 43 publications

(28 citation statements)

References 40 publications

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“…Of potential relevance to these findings, knockdown of S1R by RNAi was reported to affect expression levels of the SOC channel subunit Orai1 (Tsai et al, 2012). It has been reported that S1R overexpression or incubation with S1R agonists suppresses SOC in various cell lines (Brailoiu et al, 2016; Srivats et al, 2016). To explain these results it has been proposed that S1R may suppress SOC by binding to STIM1 and obstructing the interaction of STIM1 and Orai1 (Srivats et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease

Ryskamp

Geva

et al. 2017

Neurobiology of Disease

103

149

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The tri-nucleotide repeat expansion underlying Huntington disease (HD) results in corticostriatal synaptic dysfunction and subsequent neurodegeneration of striatal medium spiny neurons (MSNs). HD is a devastating autosomal dominant disease with no disease-modifying treatments. Pridopidine, a postulated “dopamine stabilizer”, has been shown to improve motor symptoms in clinical trials of HD. However, the target(s) and mechanism of action of pridopidine remain to be fully elucidated. As binding studies identified sigma-1 receptor (S1R) as a high-affinity receptor for pridopidine, we evaluated the relevance of S1R as a therapeutic target of pridopidine in HD. S1R is an endoplasmic reticulum - (ER) resident transmembrane protein and is regulated by ER calcium homeostasis, which is perturbed in HD. Consistent with ER calcium dysregulation, we observed striatal upregulation of S1R in aged YAC128 transgenic HD mice and HD patients. We previously demonstrated that dendritic MSN spines are lost in aged corticostriatal co-cultures from YAC128 mice. We report here that pridopidine and the chemically similar S1R agonist 3-PPP prevent MSN spine loss in aging YAC128 co-cultures. Spine protection was blocked by neuronal deletion of S1R. Pridopidine treatment suppressed supranormal ER Ca2+ release, restored ER calcium levels and reduced excessive store-operated calcium (SOC) entry in spines, which may account for its synaptoprotective effects. Normalization of ER Ca2+ levels by pridopidine was prevented by S1R deletion. To evaluate long-term effects of pridopidine, we analyzed expression profiles of calcium signaling genes. Pridopidine elevated striatal expression of calbindin and homer1a, whereas their striatal expression was reduced in aged Q175KI and YAC128 HD mouse models compared to WT. Pridopidine and 3-PPP are proposed to prevent calcium dysregulation and synaptic loss in a YAC128 corticostriatal co-culture model of HD. The actions of pridopidine were mediated by S1R and led to normalization of ER Ca2+ release, ER Ca2+ levels and spine SOC entry in YAC128 MSNs. This is a new potential mechanism of action for pridopidine, highlighting S1R as a potential target for HD therapy. Upregulation of striatal proteins that regulate calcium, including calbindin and homer1a, upon chronic therapy with pridopidine, may further contribute to long-term beneficial effects of pridopidine in HD.

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Section: Discussionmentioning

confidence: 99%

The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease

Ryskamp

Geva

et al. 2017

Neurobiology of Disease

103

149

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“…7). We recently reported that SOCE is a functional mechanism of Ca 2+ entry in RBMVEC (Brailoiu et al, 2016). Similarly, thrombin elicited SOCE in HUVEC (Sandoval et al, 2001) or in mouse lung microvascular endothelial cells (Tiruppathi et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Rat brain microvascular endothelial cells (RBMVEC) from Cell Applications, Inc (San Diego, CA) were cultured in rat brain endothelial basal medium and endothelial growth supplements, according to the manufacturer’s instructions (Cell Applications, Inc), as previously described (Altmann et al, 2015; Brailoiu et al, 2016). Cells were grown in T75 flasks coated with attachment factor (Cell Applications, Inc) until 80% confluent.…”

Section: Methodsmentioning

confidence: 99%

“…Measurements of intracellular Ca 2+ concentration, [Ca 2+ ] i , were performed as previously described (Altmann et al, 2015; Brailoiu et al, 2016). Briefly, cells were incubated with 5 μM Fura-2 AM (Molecular Probes, ThermoFisher Scientific, Waltham, MA) in Hanks Balanced Salt Solution (HBSS) at room temperature for one hour and washed with dye-free HBSS.…”

Section: Methodsmentioning

confidence: 99%

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Mechanisms of modulation of brain microvascular endothelial cells function by thrombin

et al. 2017

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Brain microvascular endothelial cells are a critical component of the blood-brain barrier. They form a tight monolayer which is essential for maintaining the brain homeostasis. Blood-derived proteases such as thrombin may enter the brain during pathological conditions like trauma, stroke, and inflammation and further disrupts the permeability of the blood-brain barrier, via incompletely characterized mechanisms. We examined the underlying mechanisms evoked by thrombin in rat brain microvascular endothelial cells (RBMVEC). Our results indicate that thrombin, acting on protease-activated receptor 1 (PAR1) increases cytosolic Ca2+ concentration in RBMVEC via Ca2+ release from endoplasmic reticulum through inositol 1,4,5-trisphosphate receptors and Ca2+ influx from extracellular space. Thrombin increases nitric oxide production; the effect is abolished by inhibition of the nitric oxide synthase or by antagonism of PAR1 receptors. In addition, thrombin increases mitochondrial and cytosolic reactive oxygen species production via PAR1-dependent mechanisms. Immunocytochemistry studies indicate that thrombin increases F-actin stress fibers, and disrupts the tight junctions. Thrombin increased the RBMVEC permeability assessed by a fluorescent flux assay. Taken together, our results indicate multiple mechanisms by which thrombin modulates the function of RBMVEC and may contribute to the blood-brain barrier dysfunction.

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“…Thus, the Sig-1R may interact with the plasma membrane proteins via Sig-1R’s proximity to the plasma membrane. Finally, a recent report suggested that the Sig-1R activation inhibits store-operated Ca 2+ (SOCE) entry effects in rat brain microvascular endothelial cells [48]. However, the physical interaction, if any, between the Sig-1R and the SOCE protein complex ORAI1 or STIM1 has yet to be established.…”

Section: Sig-1r–interacting Proteins Per Experimental Demonstrations mentioning

confidence: 99%

The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems

Nakamura

et al. 2016

Trends in Pharmacological Sciences

259

257

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The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum (ER) protein resides specifically at the interface between ER and mitochondria, called the MAM, where the Sig-1R is recently reported to be involved in certain CNS diseases. In addition to being able to translocate to the plasma membrane to interact with ion channels and other receptors, the Sig-1R is found to exist at the nuclear envelope where it recruits chromatin-remodeling factors to affect the transcription of genes. As well, thorough experimental and bioinformatic means, Sig-1Rs are reported to interact with other membranous or soluble proteins at other loci, including the cytosol. We propose that the Sig-1R is a pluripotent modulator with resultant multiple functional manifestations in the living system.

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

Cited by 43 publications

References 40 publications

The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease

The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease

Mechanisms of modulation of brain microvascular endothelial cells function by thrombin

The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems

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