Korean J Physiol Pharmacol.  2024 Jan;28(1):93-103. 10.4196/kjpp.2024.28.1.93.

Store-operated calcium entry in the satellite glial cells of rat sympathetic ganglia

• Kim S
• Kang SJ
• Nguyen HS
• Jeong SW

• KMID: 2550292
• DOI: http://doi.org/10.4196/kjpp.2024.28.1.93

Abstract

Satellite glial cells (SGCs), a major type of glial cell in the autonomic ganglia, closely envelop the cell body and even the synaptic regions of a single neuron with a very narrow gap. This structurally unique organization suggests that autonomic neurons and SGCs may communicate reciprocally. Glial Ca²⁺ signaling is critical for controlling neural activity. Here, for the first time we identified the machinery of store-operated Ca²⁺ entry (SOCE) which is critical for cellular Ca²⁺ homeostasis in rat sympathetic ganglia under normal and pathological states. Quantitative realtime PCR and immunostaining analyses showed that Orai1 and stromal interaction molecules 1 (STIM1) proteins are the primary components of SOCE machinery in the sympathetic ganglia. When the internal Ca²⁺ stores were depleted in the absence of extracellular Ca²⁺ , the number of plasmalemmal Orai1 puncta was increased in neurons and SGCs, suggesting activation of the Ca²⁺ entry channels. Intracellular Ca²⁺ imaging revealed that SOCE was present in SGCs and neurons; however, the magnitude of SOCE was much larger in the SGCs than in the neurons. The SOCE was significantly suppressed by GSK7975A, a selective Orai1 blocker, and Pyr6, a SOCE blocker. Lipopolysaccharide (LPS) upregulated the glial fibrillary acidic protein and Toll-like receptor 4 in the sympathetic ganglia. Importantly, LPS attenuated SOCE via downregulating Orai1 and STIM1 expression. In conclusion, sympathetic SGCs functionally express the SOCE machinery, which is indispensable for intracellular Ca²⁺ signaling. The SOCE is highly susceptible to inflammation, which may affect sympathetic neuronal activity and thereby autonomic output.

Keyword

Calcium signaling; Ganglia, sympathetic; Inflammation; Lipopolysaccharide; Satellite glial cell

Figure

• 

  Fig. 1 Identification of the components of SOCE machinery in neurons and SGC units of rat sympathetic ganglia. (A, a) H&E staining to demonstrate the close localization of SGCs around the large soma of an SCG neuron. (A, b) Kir4.1-positive SGCs (arrows) enveloping SCG neurons (n). (A, c-d) DIC and immunofluorescent images of a neuron-SGC unit in the culture. SGCs showed Kir4.1-IR (arrow). DAPI was used to stain the nuclei of neuron and SGC. Scale bars = 10 μM. (B) Relative mRNA expressions of Orai and STIM, the SOCE components in sympathetic ganglia. The number of experiments is indicated in parentheses. (C) Representative immunofluorescent images of Orai1 (green) and STIM1 (red) distribution in a sympathetic neuron-SGC unit. DAPI was used to stain the nuclei of both neuron and SGC. Confocal images of the cells were captured before and after a 10-min treatment with 30 μM CPA. ER Ca2+ depletion with CPA induced the mobilization of STIM1-Orai1 aggregates, resulting in the assembly of prominent puncta formation in the cell surfaces of a neuron-SGC unit. Scale bars = 10 μM. (D, E). Summary of the number of Orai1 puncta in neuron-SGC units. Vehicle DMSO-treated (VEH) and CPA-treated (CPA) groups were compared (n = 54–60 cells from 5 wells per group). The data are presented as means ± SEM. Unpaired t-test, ***p < 0.001. SOCE, store-operated calcium entry; SGC, satellite glial cell; SCG, superior cervical ganglia; DIC, differential interference contrast; DAPI, 4,6-diamino-2-phenylindole dihydrochloride; STIM, stromal interaction molecule; CPA, cyclopiazonic acid; ER, endoplasmic reticulum; DMSO, dimethyl sulfoxide.

• 

  Fig. 2 Measurement of SOCE in both neurons and SGCs of sympathetic ganglia. (A) The digital images displaying a neuron-SGC unit (left), a 340 nm/380 nm ratio at the resting basal state (middle), and SOCE induction (right). (B) Representative traces of CPA (30 μM)-induced depletion of Ca2+ stores in the absence of external Ca2+ and the subsequent secondary Ca2+ influx (SOCE) via the activated CRAC by CPA in the presence of external Ca2+ (2 mM) in a neuron-SGC unit. The area under the curve (AUC) of the Ca2+ influx traces during SOCE, referred to AUC SOCE was measured in both SGCs and neurons. (C) Summary of AUC SOCE in both SGCs and neurons. Unpaired Student’s t-test, ***p < 0.001. (D, F) Representative traces demonstrating pharmacological inhibition of SOCE with GSK7975A (1 μM for 1 h, Orai1 inhibitor) and Pyr6 (3 μM for 1 h, SOCE inhibitor) in a neuron-SGC unit. (E, G) Summary of AUC SOCE in both control (VEH) and inhibitor-treated SGCs and neurons. The data are presented as means ± SEM. The number of the tested cells is indicated in parentheses. One-way ANOVA followed by post-hoc Tukey’s multiple comparison test, ***p < 0.001. SOCE, store-operated calcium entry; SGC, satellite glial cell; CPA, cyclopiazonic acid; CRAC, calcium release-activated calcium channel.

• 

  Fig. 3 LPS-induced upregulation of GFAP and TLR4 in sympathetic ganglia. (A, B) Real-time PCR analysis to assess the transcripts encoding GFAP and TLR4 in the sympathetic ganglia collected from rats with and without LPS injection (2 mg/kg, i.p., 24 h). (C) Confocal images depicting changes in GFAP expression in the SGCs of sympathetic ganglia 24 h after LPS injection. Scale bars = 10 μm. (D) Immunoblots of SCG collected from rats 24 h after injection of either vehicle or LPS in vivo. (E, F) Summary of the LPS-induced changes in the expression of GFAP and TLR4 proteins in the SCG. (G) Confocal images showing the localization and changes in TLR4 immunoreactivity in the control (VEH) and LPS (1 μg/ml, 24 h)-treated neuron-SGC units. Scale bars = 10 μm. Data are presented as means ± SEM. The number of experiments is indicated in parentheses. Unpaired Student’s t-test, *p < 0.05, **p < 0.01, ***p < 0.001. LPS, lipopolysaccharide; GFAP, glial fibrillary acidic protein; TLR4, toll-like receptor 4; SGC, satellite glial cell; SCG, superior cervical ganglia; i.p., intraperitoneal; DAPI, 4,6-diamino-2-phenylindole dihydrochloride.

• 

  Fig. 4 LPS decreased SOCE by downregulating Orai 1 and STIM1 in the sympathetic ganglia. (A, B) Summary of the relative expression of transcripts encoding STIM1 and Orai1. (C) Immunoblots of Orai1 and STIM1 protein expression in rat SCG 24 h after either vehicle (VEH) or LPS injection in vivo. (D, E) Summary of the relative expression of Orai1 and STIM1 proteins. (F, H) Representative traces of SOCE in SGCs (F) and neurons (H) following treatment with either vehicle or LPS (1 μg/ml, 24 h in vitro). (G, I) Summary of the LPS-induced changes in AUC SOCE in both SGCs and neurons (n = 17–28 cells). The data are presented as means ± SEM. The number of experiments is indicated in parentheses. Unpaired Student’s t-test, *p < 0.05, **p < 0.01, ***p < 0.001. LPS, lipopolysaccharide; SOCE, store-operated calcium entry; STIM, stromal interaction molecule; SCG, superior cervical ganglia; SGC, satellite glial cell; CPA, cyclopiazonic acid; AUC, area under the curve.

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