Axonal Endoplasmic Reticulum Ca2+ Content Controls Release Probability in CNS Nerve Terminals

Juan-Sanz, Jaime de; Holt, Graham T.; Schreiter, Eric R.; Juan, Fernando de; Kim, Douglas S.; Ryan, Timothy A.

doi:10.1016/j.neuron.2017.01.010

Cited by 244 publications

(299 citation statements)

References 79 publications

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“…Conversely, mitochondrial calcium, which was assayed in macrophages transduced the mitochondrial calcium indicator 2x-COX8-GCaMP6f (Mito-GCaMP6f), was higher in AC + Cre+/− vs. AC + Cre+/− macrophages (Figures 5B and S4F). Finally, ER calcium was assayed in macrophages transduced with ER-GCaMP6f-150 (de Juan-Sanz et al, 2017). As predicted (Cuttell et al, 2008; Gronski et al, 2009), ACs led to an early decrease in ER calcium.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial Fission Promotes the Continued Clearance of Apoptotic Cells by Macrophages

Wang

Subramanian

Yurdagul

et al. 2017

Cell

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278

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SUMMARY Clearance of apoptotic cells (ACs) by phagocytes (efferocytosis) prevents post-apoptotic necrosis and dampens inflammation. Defective efferocytosis drives important diseases, including atherosclerosis. For efficient efferocytosis, phagocytes must be able to internalize multiple ACs. We show here that uptake of multiple ACs by macrophages requires dynamin-related protein 1 (Drp1)-mediated mitochondrial fission, which is triggered by AC uptake. When mitochondrial fission is disabled, AC-induced increase in cytosolic calcium is blunted owing to mitochondrial calcium sequestration, and calcium-dependent phagosome formation around secondarily encountered ACs is impaired. These defects can be corrected by silencing the mitochondrial calcium uniporter (MCU). Mice lacking myeloid Drp1 showed defective efferocytosis and its pathologic consequences in the thymus after dexamethasone treatment and in advanced atherosclerotic lesions in fat-fed Ldlr−/ − mice. Thus, mitochondrial fission in response to AC uptake is a critical process that enables macrophages to clear multiple ACs and to avoid the pathologic consequences of defective efferocytosis in vivo.

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Section: Resultsmentioning

confidence: 99%

Mitochondrial Fission Promotes the Continued Clearance of Apoptotic Cells by Macrophages

Wang

Subramanian

Yurdagul

et al. 2017

Cell

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278

254

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“…Both stromal interaction molecule (STIM) and ORAi proteins, key players in SOCE, and ryanodine receptors, ER-localized Ca 2+ channels responsible for Ca 2+ -induced Ca 2+ release at the ER-PM junction in muscle (75,77), are expressed in neurons (78,79). Similarly, isoforms of junctophilin, another integral protein of the ER membrane that binds the PM in trans and functions as an accessory factor of the ryanodine receptors at muscle triads, are expressed in neurons (80)(81)(82).…”

Section: Discussionmentioning

confidence: 99%

Contacts between the endoplasmic reticulum and other membranes in neurons

Whiteus

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

434

501

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Close appositions between the membrane of the endoplasmic reticulum (ER) and other intracellular membranes have important functions in cell physiology. These include lipid homeostasis, regulation of Ca 2+ dynamics, and control of organelle biogenesis and dynamics. Although these membrane contacts have previously been observed in neurons, their distribution and abundance have not been systematically analyzed. Here, we have used focused ion beam-scanning electron microscopy to generate 3D reconstructions of intracellular organelles and their membrane appositions involving the ER (distance ≤30 nm) in different neuronal compartments. ER-plasma membrane (PM) contacts were particularly abundant in cell bodies, with large, flat ER cisternae apposed to the PM, sometimes with a notably narrow lumen (thin ER). Smaller ER-PM contacts occurred throughout dendrites, axons, and in axon terminals. ER contacts with mitochondria were abundant in all compartments, with the ER often forming a network that embraced mitochondria. Small focal contacts were also observed with tubulovesicular structures, likely to be endosomes, and with sparse multivesicular bodies and lysosomes found in our reconstructions. Our study provides an anatomical reference for interpreting information about interorganelle communication in neurons emerging from functional and biochemical studies.FIB-SEM | thin ER | Stim1 | spine apparatus | subsurface cisternae

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“…Endoplasmic reticulum is an important organelle of calcium storage, multicellular biofibroma synthesis, protein folding and secretion [17] [18]. Cell metabolism is related to endoplasmic reticulum structure, so the more exuberant metabolism, the more rich structure.…”

Section: Discussionmentioning

confidence: 99%

Effects of Endoplasmic Reticulum Stress on Pulmonary Hypertension in Rat Induced by Chronic Hypoxia and Hypercapnia

Zhang¹,

Zhang²,

Wu³

et al. 2018

JBM

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Objective: To observe the pulmonary vascular remodeling in rats with pulmonary hypertension induced by hypoxia and hypercapnia, and to explore the role of endoplasmic reticulum stress in pulmonary hypertension. Methods: 1) 40 SD rats were randomly divided into four groups: normoxic control group (N), hypoxia hypercapnia group (HH), endoplasmic reticulum stress (ERS) inhibitor 4-phenyl butyric acid group (4-PBA), ERS pathway agonist tunicamycin group (TM). 2) The mean pulmonary arterial pressure (mPAP) and the right ventricular hypertrophy index (RV/(LV + S)) were measured in each group. 3) Identification of pulmonary artery smooth muscle cells (PASMCs) in each group by immunofluorescence α-SMA. 4) Morphological changes of lung tissue and pulmonary artery were observed by electron microscope. 5) The apoptotic index of PASMCs in each group was detected by TUNEL. 6) Reverse transcription polymerase chain reaction (RT-PCR) and Western Blot (WB) were used to detect the expression of ERS related protein and mRNA (GRP78, CHOP, JNK, Caspase-12) in each group. Results: 1) Compared with the N group, the mPAP, RV/(LV + S) and vascular wall area (WA)/total area (TA) value of HH group, 4-PBA group and TM group were increased (P < 0.01), and the vascular lumen area (LA)/TA values, PASMCs apoptosis index were significantly decreased. GRP78, CHOP, JNK, Caspase-12 expression were increased, and the differences were statistically significant. 2) Compared with the HH group, the mPAP, RV/(LV + S) and WA/TA of 4-PBA group were decreased (P < 0.01); the LA/TA value and PASMCs apoptosis index were increased (P < 0.05); and the mRNA and protein expression of CHOP, JNK, Caspase-12 and GRP78 had a significant decrease (P < 0.05). 3) Compared with the HH, the mPAP, RV/(LV + S) and WA/TA of TM group were increased (P < 0.05, P < 0.01), while LA/TA were decreased (P < 0.01); and PASMCs apoptotic index was increased (P < 0.01). Meanwhile, the mRNA expression of Caspase-12, CHOP, JNK and GRP78 was increased to varying degrees (P < 0.05), and the protein expression of Caspase-12, CHOP and JNK was also increased significantly (P < 0.01). Conclusion: Hypoxia and hypercapnia induced pulmonary vascular remodeling may be related to the proliferation of PASMCs, and ERS related factors (JNK, Caspase12 and CHOP) are involved in the regulation of hypoxic hypercapnia.

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Axonal Endoplasmic Reticulum Ca2+ Content Controls Release Probability in CNS Nerve Terminals

Cited by 244 publications

References 79 publications

Mitochondrial Fission Promotes the Continued Clearance of Apoptotic Cells by Macrophages

Mitochondrial Fission Promotes the Continued Clearance of Apoptotic Cells by Macrophages

Contacts between the endoplasmic reticulum and other membranes in neurons

Effects of Endoplasmic Reticulum Stress on Pulmonary Hypertension in Rat Induced by Chronic Hypoxia and Hypercapnia

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