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Neuronal microRNAs safeguard ER Ca2+ homeostasis and attenuate the unfolded protein response upon stress

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Abstract

Ca2+ is a critical mediator of neurotransmitter release, synaptic plasticity, and gene expression, but also excitotoxicity. Ca2+ signaling and homeostasis are coordinated by an intricate network of channels, pumps, and calcium-binding proteins, which must be rapidly regulated at all expression levels. Τhe role of neuronal miRNAs in regulating ryanodine receptors (RyRs) and inositol 1,4,5-triphosphate receptors (IP3Rs) was investigated to understand the underlying mechanisms that modulate ER Ca2+ release. RyRs and IP3Rs are critical in mounting and propagating cytosolic Ca2+ signals by functionally linking the ER Ca2+ content, while excessive ER Ca2+ release via these receptors is central to the pathophysiology of a wide range of neurological diseases. Herein, two brain-restricted microRNAs, miR-124-3p and miR-153-3p, were found to bind to RyR1-3 and IP3R3 3′UTRs, and suppress their expression at both the mRNA and protein level. Ca2+ imaging studies revealed that overexpression of these miRNAs reduced ER Ca2+ release upon RyR/IP3R activation, but had no effect on [Ca2+]i under resting conditions. Interestingly, treatments that cause excessive ER Ca2+ release decreased expression of these miRNAs and increased expression of their target ER Ca2+ channels, indicating interdependence of miRNAs, RyRs, and IP3Rs in Ca2+ homeostasis. Furthermore, by maintaining the ER Ca2+ content, miR-124 and miR-153 reduced cytosolic Ca2+ overload and preserved protein-folding capacity by attenuating PERK signaling. Overall, this study shows that miR-124-3p and miR-153-3p fine-tune ER Ca2+ homeostasis and alleviate ER stress responses.

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Abbreviations

miRNAs:

MicroRNAs

UTR:

Untranslated region

ER:

Endoplasmic reticulum

CNS:

Central nervous system

Ca2+ :

Calcium

RyRs:

Ryanodine receptors

IP3Rs:

Inositol 1,4,5-triphosphate receptors

CICR:

Ca2+-induced Ca2+ release

UPR:

Unfolded protein response

Tm:

Tunicamycin

CAFF:

Caffeine

CCh:

Carbachol

Tg:

Thapsigargin

TuD:

Tough Decoy

PERK:

Protein kinase RNA (PKR)-like endoplasmic reticulum kinase

IRE1α:

Inositol-requiring enzyme 1 alpha

ATF6:

Activating transcription factor 6

GRP78/Bip:

Glucose-regulated protein 78/binding-immunoglobulin protein

eIF2α:

Eukaryotic initiation factor-alpha

ATF4:

Activating transcription factor 4

CHOP/DDIT3:

CCAAT/enhancer-binding protein (C/EBP) homologous protein/DNA damage-inducible transcript 3

XBP1u/s:

Unspliced/spliced X-box-binding protein 1

References

  1. Doxakis E (2013) Principles of miRNA-target regulation in metazoan models. Int J Mol Sci 14(8):16280–16302. https://doi.org/10.3390/ijms140816280 (Epub 2013/08/24. PubMed PMID: 23965954)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Yoo AS, Staahl BT, Chen L, Crabtree GR (2009) MicroRNA-mediated switching of chromatin-remodelling complexes in neural development. Nature 460(7255):642–646. https://doi.org/10.1038/nature08139 (Epub 2009/06/30. PubMed PMID: 19561591; PubMed Central PMCID: PMC2921580)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Yoo AS, Sun AX, Li L, Shcheglovitov A, Portmann T, Li Y et al (2011) MicroRNA-mediated conversion of human fibroblasts to neurons. Nature 476(7359):228–231. https://doi.org/10.1038/nature10323 (Epub 2011/07/15. PubMed PMID: 21753754)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J et al (2005) Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433(7027):769–773. https://doi.org/10.1038/nature03315 (Epub 2005/02/03. PubMed PMID: 15685193)

    Article  CAS  PubMed  Google Scholar 

  5. Makeyev EV, Zhang J, Carrasco MA, Maniatis T (2007) The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Mol Cell 27(3):435–448. https://doi.org/10.1016/j.molcel.2007.07.015 (PubMed PMID: 17679093; PubMed Central PMCID: PMC3139456)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mokabber H, Najafzadeh N, Mohammadzadeh VM (2019) miR-124 promotes neural differentiation in mouse bulge stem cells by repressing Ptbp1 and Sox9. J Cell Physiol 234(6):8941–8950. https://doi.org/10.1002/jcp.27563 (Epub 2018/11/13. PubMed PMID: 30417370)

    Article  CAS  PubMed  Google Scholar 

  7. Xue Q, Yu C, Wang Y, Liu L, Zhang K, Fang C et al (2016) miR-9 and miR-124 synergistically affect regulation of dendritic branching via the AKT/GSK3β pathway by targeting Rap2a. Sci Rep 6:26781. https://doi.org/10.1038/srep26781 (Epub 2016/05/26. PubMed PMID: 27221778; PubMed Central PMCID: PMCPMC4879704)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Han D, Dong X, Zheng D, Nao J (2019) MiR-124 and the underlying therapeutic promise of neurodegenerative disorders. Front Pharmacol 10:1555. https://doi.org/10.3389/fphar.2019.01555 (Epub 2020/02/06. PubMed PMID: 32009959; PubMed Central PMCID: PMCPMC6978711)

    Article  CAS  PubMed  Google Scholar 

  9. Mishima T, Mizuguchi Y, Kawahigashi Y, Takizawa T, Takizawa T (2007) RT-PCR-based analysis of microRNA (miR-1 and -124) expression in mouse CNS. Brain Res 1131(1):37–43. https://doi.org/10.1016/j.brainres.2006.11.035 (Epub 2006/12/22. PubMed PMID: 17182009)

    Article  CAS  PubMed  Google Scholar 

  10. Sun Y, Luo ZM, Guo XM, Su DF, Liu X (2015) An updated role of microRNA-124 in central nervous system disorders: a review. Front Cell Neurosci 9:193. https://doi.org/10.3389/fncel.2015.00193 (Epub 2015/06/05. PubMed PMID: 26041995; PubMed Central PMCID: PMCPMC4438253)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fischbach SJ, Carew TJ (2009) MicroRNAs in memory processing. Neuron 63(6):714–716. https://doi.org/10.1016/j.neuron.2009.09.007 (Epub 2009/09/26. PubMed PMID: 19778498)

    Article  CAS  PubMed  Google Scholar 

  12. Rajasethupathy P, Fiumara F, Sheridan R, Betel D, Puthanveettil SV, Russo JJ et al (2009) Characterization of small RNAs in Aplysia reveals a role for miR-124 in constraining synaptic plasticity through CREB. Neuron 63(6):803–817. https://doi.org/10.1016/j.neuron.2009.05.029 (Epub 2009/09/26. PubMed PMID: 19778509; PubMed Central PMCID: PMC2875683)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Soreq H, Wolf Y (2011) NeurimmiRs: microRNAs in the neuroimmune interface. Trends Mol Med 17(10):548–555. https://doi.org/10.1016/j.molmed.2011.06.009 (Epub 2011/08/05. PubMed PMID: 21813326)

    Article  CAS  PubMed  Google Scholar 

  14. Fang M, Wang J, Zhang X, Geng Y, Hu Z, Rudd JA et al (2012) The miR-124 regulates the expression of BACE1/beta-secretase correlated with cell death in Alzheimer’s disease. Toxicol Lett 209(1):94–105. https://doi.org/10.1016/j.toxlet.2011.11.032 (Epub 2011/12/20. PubMed PMID: 22178568)

    Article  CAS  PubMed  Google Scholar 

  15. Doeppner TR, Doehring M, Bretschneider E, Zechariah A, Kaltwasser B, Muller B et al (2013) MicroRNA-124 protects against focal cerebral ischemia via mechanisms involving Usp14-dependent REST degradation. Acta Neuropathol 126(2):251–265. https://doi.org/10.1007/s00401-013-1142-5 (PubMed PMID: 23754622)

    Article  CAS  PubMed  Google Scholar 

  16. Wang H, Ye Y, Zhu Z, Mo L, Lin C, Wang Q et al (2016) MiR-124 regulates apoptosis and autophagy process in MPTP model of Parkinson’s disease by targeting to bim. Brain Pathol 26(2):167–176. https://doi.org/10.1111/bpa.12267 (Epub 2015/05/16. PubMed PMID: 25976060)

    Article  CAS  PubMed  Google Scholar 

  17. Yip PK, Bowes AL, Hall JCE, Burguillos MA, Ip THR, Baskerville T et al (2019) Docosahexaenoic acid reduces microglia phagocytic activity via miR-124 and induces neuroprotection in rodent models of spinal cord contusion injury. Hum Mol Genet 28(14):2427–2448. https://doi.org/10.1093/hmg/ddz073 (PubMed PMID: 30972415)

    Article  CAS  PubMed  Google Scholar 

  18. Paschou M, Maier L, Papazafiri P, Selescu T, Dedos SG, Babes A et al (2020) Neuronal microRNAs modulate TREK two-pore domain K(+) channel expression and current density. RNA Biol 17(5):651–662. https://doi.org/10.1080/15476286.2020.1722450 (PubMed PMID: 31994436; PubMed Central PMCID: PMC7237132)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gong X, Wang H, Ye Y, Shu Y, Deng Y, He X et al (2016) miR-124 regulates cell apoptosis and autophagy in dopaminergic neurons and protects them by regulating AMPK/mTOR pathway in Parkinson’s disease. Am J Transl Res 8(5):2127–2137 (Epub 2016/06/28. PubMed PMID: 27347320; PubMed Central PMCID: PMCPMC4891425)

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Dong RF, Zhang B, Tai LW, Liu HM, Shi FK, Liu NN (2018) The Neuroprotective role of MiR-124-3p in a 6-hydroxydopamine-induced cell model of Parkinson’s disease via the regulation of ANAX5. J Cell Biochem 119(1):269–277. https://doi.org/10.1002/jcb.26170 (Epub 2017/05/26. PubMed PMID: 28543594)

    Article  CAS  PubMed  Google Scholar 

  21. Geng L, Liu W, Chen Y (2017) miR-124-3p attenuates MPP(+)-induced neuronal injury by targeting STAT3 in SH-SY5Y cells. Exp Biol Med (Maywood) 242(18):1757–1764. https://doi.org/10.1177/1535370217734492 (Epub 2017/09/30. PubMed PMID: 28958159; PubMed Central PMCID: PMCPMC5714150)

    Article  CAS  Google Scholar 

  22. Du X, Huo X, Yang Y, Hu Z, Botchway BOA, Jiang Y et al (2017) miR-124 downregulates BACE 1 and alters autophagy in APP/PS1 transgenic mice. Toxicol Lett 280:195–205. https://doi.org/10.1016/j.toxlet.2017.08.082 (Epub 2017/09/05. PubMed PMID: 28867212)

    Article  CAS  PubMed  Google Scholar 

  23. Slota JA, Booth SA (2019) MicroRNAs in neuroinflammation: implications in disease pathogenesis, biomarker discovery and therapeutic applications. Noncoding RNA 5(2):35. https://doi.org/10.3390/ncrna5020035 (PubMed PMID: 31022830)

    Article  CAS  PubMed Central  Google Scholar 

  24. Ghafouri-Fard S, Shoorei H, Bahroudi Z, Abak A, Majidpoor J, Taheri M (2021) An update on the role of miR-124 in the pathogenesis of human disorders. Biomed Pharmacother 135:111198. https://doi.org/10.1016/j.biopha.2020.111198 (Epub 2021/01/08. PubMed PMID: 33412388)

    Article  CAS  PubMed  Google Scholar 

  25. Fowler A, Thomson D, Giles K, Maleki S, Mreich E, Wheeler H et al (2011) miR-124a is frequently down-regulated in glioblastoma and is involved in migration and invasion. Eur J Cancer 47(6):953–963. https://doi.org/10.1016/j.ejca.2010.11.026 (PubMed PMID: 21196113)

    Article  CAS  PubMed  Google Scholar 

  26. Silber J, Lim DA, Petritsch C, Persson AI, Maunakea AK, Yu M et al (2008) miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med 6:14. https://doi.org/10.1186/1741-7015-6-14 (Epub 2008/06/26. PubMed PMID: 18577219; PubMed Central PMCID: PMCPMC2443372)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sun Y, Li Q, Gui H, Xu DP, Yang YL, Su DF et al (2013) MicroRNA-124 mediates the cholinergic anti-inflammatory action through inhibiting the production of pro-inflammatory cytokines. Cell Res 23(11):1270–1283. https://doi.org/10.1038/cr.2013.116 (Epub 2013/08/28. PubMed PMID: 23979021; PubMed Central PMCID: PMCPMC3817544)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mattson MP (2007) Calcium and neurodegeneration. Aging Cell 6(3):337–350. https://doi.org/10.1111/j.1474-9726.2007.00275.x (Epub 2007/03/03. PubMed PMID: 17328689)

    Article  CAS  PubMed  Google Scholar 

  29. Doxakis E (2010) Post-transcriptional regulation of alpha-synuclein expression by mir-7 and mir-153. J Biol Chem 285(17):12726–12734. https://doi.org/10.1074/jbc.M109.086827 (Epub 2010/01/29. PubMed PMID: 20106983; PubMed Central PMCID: PMCPMC2857101)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Qiao J, Zhao J, Chang S, Sun Q, Liu N, Dong J et al (2020) MicroRNA-153 improves the neurogenesis of neural stem cells and enhances the cognitive ability of aged mice through the notch signaling pathway. Cell Death Differ 27(2):808–825. https://doi.org/10.1038/s41418-019-0388-4 (PubMed PMID: 31296962; PubMed Central PMCID: PMC7206122)

    Article  CAS  PubMed  Google Scholar 

  31. Stappert L, Borghese L, Roese-Koerner B, Weinhold S, Koch P, Terstegge S et al (2013) MicroRNA-based promotion of human neuronal differentiation and subtype specification. PLoS ONE 8(3):e59011. https://doi.org/10.1371/journal.pone.0059011 (PubMed PMID: 23527072; PubMed Central PMCID: PMC3601127)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Xu C, Wang C, Meng Q, Gu Y, Wang Q, Xu W et al (2019) miR153 promotes neural differentiation in the mouse hippocampal HT22 cell line and increases the expression of neuronspecific enolase. Mol Med Rep 20(2):1725–1735. https://doi.org/10.3892/mmr.2019.10421 (Epub 2019/07/02. PubMed PMID: 31257504; PubMed Central PMCID: PMCPMC6625396)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Liang C, Zhu H, Xu Y, Huang L, Ma C, Deng W et al (2012) MicroRNA-153 negatively regulates the expression of amyloid precursor protein and amyloid precursor-like protein 2. Brain Res 1455:103–113. https://doi.org/10.1016/j.brainres.2011.10.051 (PubMed PMID: 22510281)

    Article  CAS  PubMed  Google Scholar 

  34. Long JM, Ray B, Lahiri DK (2012) MicroRNA-153 physiologically inhibits expression of amyloid-beta precursor protein in cultured human fetal brain cells and is dysregulated in a subset of Alzheimer disease patients. J Biol Chem 287(37):31298–31310. https://doi.org/10.1074/jbc.M112.366336 (Epub 2012/06/27. PubMed PMID: 22733824; PubMed Central PMCID: PMCPMC3438960)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wei C, Thatcher EJ, Olena AF, Cha DJ, Perdigoto AL, Marshall AF et al (2013) miR-153 regulates SNAP-25, synaptic transmission, and neuronal development. PLoS ONE 8(2):e57080. https://doi.org/10.1371/journal.pone.0057080 (PubMed PMID: 23451149; PubMed Central PMCID: PMC3581580)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Banks SA, Pierce ML, Soukup GA (2020) Sensational microRNAs: neurosensory roles of the microRNA-183 family. Mol Neurobiol 57(1):358–371. https://doi.org/10.1007/s12035-019-01717-3 (Epub 2019/07/31. PubMed PMID: 31359323)

    Article  CAS  PubMed  Google Scholar 

  37. Dambal S, Shah M, Mihelich B, Nonn L (2015) The microRNA-183 cluster: the family that plays together stays together. Nucleic Acids Res 43(15):7173–7188. https://doi.org/10.1093/nar/gkv703 (PubMed PMID: 26170234; PubMed Central PMCID: PMC4551935)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Schluter T, Berger C, Rosengauer E, Fieth P, Krohs C, Ushakov K et al (2018) miR-96 is required for normal development of the auditory hindbrain. Hum Mol Genet 27(5):860–874. https://doi.org/10.1093/hmg/ddy007 (PubMed PMID: 29325119)

    Article  CAS  PubMed  Google Scholar 

  39. Xiang L, Chen XJ, Wu KC, Zhang CJ, Zhou GH, Lv JN et al (2017) miR-183/96 plays a pivotal regulatory role in mouse photoreceptor maturation and maintenance. Proc Natl Acad Sci USA 114(24):6376–6381. https://doi.org/10.1073/pnas.1618757114 (PubMed PMID: 28559309; PubMed Central PMCID: PMC5474811)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Chen HP, Zhou W, Kang LM, Yan H, Zhang L, Xu BH et al (2014) Intrathecal miR-96 inhibits Nav1.3 expression and alleviates neuropathic pain in rat following chronic construction injury. Neurochem Res 39(1):76–83. https://doi.org/10.1007/s11064-013-1192-z (PubMed PMID: 24234845)

    Article  CAS  PubMed  Google Scholar 

  41. Dong Y, Han LL, Xu ZX (2018) Suppressed microRNA-96 inhibits iNOS expression and dopaminergic neuron apoptosis through inactivating the MAPK signaling pathway by targeting CACNG5 in mice with Parkinson’s disease. Mol Med 24(1):61. https://doi.org/10.1186/s10020-018-0059-9 (PubMed PMID: 30486773; PubMed Central PMCID: PMC6263543)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kinoshita C, Aoyama K, Matsumura N, Kikuchi-Utsumi K, Watabe M, Nakaki T (2014) Rhythmic oscillations of the microRNA miR-96-5p play a neuroprotective role by indirectly regulating glutathione levels. Nat Commun 5:3823. https://doi.org/10.1038/ncomms4823 (PubMed PMID: 24804999; PubMed Central PMCID: PMC4024755)

    Article  CAS  PubMed  Google Scholar 

  43. Kye MJ, Niederst ED, Wertz MH, Goncalves Ido C, Akten B, Dover KZ et al (2014) SMN regulates axonal local translation via miR-183/mTOR pathway. Hum Mol Genet 23(23):6318–6331. https://doi.org/10.1093/hmg/ddu350 (PubMed PMID: 25055867; PubMed Central PMCID: PMC4271102)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ubhi K, Rockenstein E, Kragh C, Inglis C, Spencer B, Michael S et al (2014) Widespread microRNA dysregulation in multiple system atrophy—disease-related alteration in miR-96. Eur J Neurosci 39(6):1026–1041. https://doi.org/10.1111/ejn.12444 (PubMed PMID: 24304186; PubMed Central PMCID: PMC4052839)

    Article  PubMed  Google Scholar 

  45. Berridge MJ (1998) Neuronal calcium signaling. Neuron 21(1):13–26. https://doi.org/10.1016/s0896-6273(00)80510-3 (Epub 1998/08/11. PubMed PMID: 9697848)

    Article  CAS  PubMed  Google Scholar 

  46. Kawamoto EM, Vivar C, Camandola S (2012) Physiology and pathology of calcium signaling in the brain. Front Pharmacol 3:61. https://doi.org/10.3389/fphar.2012.00061 (PubMed PMID: 22518105; PubMed Central PMCID: PMC3325487)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Berridge MJ, Lipp P, Bootman MD (2000) The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 1(1):11–21. https://doi.org/10.1038/35036035 (Epub 2001/06/20. PubMed PMID: 11413485)

    Article  CAS  PubMed  Google Scholar 

  48. Carreras-Sureda A, Pihan P, Hetz C (2018) Calcium signaling at the endoplasmic reticulum: fine-tuning stress responses. Cell Calcium 70:24–31. https://doi.org/10.1016/j.ceca.2017.08.004 (Epub 2017/10/22. PubMed PMID: 29054537)

    Article  CAS  PubMed  Google Scholar 

  49. Chen S, Novick P, Ferro-Novick S (2013) ER structure and function. Curr Opin Cell Biol 25(4):428–433. https://doi.org/10.1016/j.ceb.2013.02.006 (Epub 2013/03/13. PubMed PMID: 23478217; PubMed Central PMCID: PMCPMC5614462)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Berridge MJ (2002) The endoplasmic reticulum: a multifunctional signaling organelle. Cell Calcium 32(5–6):235–249. https://doi.org/10.1016/s0143416002001823 (Epub 2003/01/25. PubMed PMID: 12543086)

    Article  CAS  PubMed  Google Scholar 

  51. Primeau JO, Armanious GP, Fisher ME, Young HS (2018) The SarcoEndoplasmic reticulum calcium ATPase. Subcell Biochem 87:229–258. https://doi.org/10.1007/978-981-10-7757-9_8 (Epub 2018/02/22. PubMed PMID: 29464562)

    Article  CAS  PubMed  Google Scholar 

  52. Fill M (2003) Mechanisms that turn-off intracellular calcium release channels. Front Biosci 8:d46-54. https://doi.org/10.2741/924 (Epub 2002/11/29. PubMed PMID: 12456314)

    Article  CAS  PubMed  Google Scholar 

  53. Hakamata Y, Nakai J, Takeshima H, Imoto K (1992) Primary structure and distribution of a novel ryanodine receptor/calcium release channel from rabbit brain. FEBS Lett 312(2–3):229–235. https://doi.org/10.1016/0014-5793(92)80941-9 (PubMed PMID: 1330694)

    Article  CAS  PubMed  Google Scholar 

  54. Furuichi T, Furutama D, Hakamata Y, Nakai J, Takeshima H, Mikoshiba K (1994) Multiple types of ryanodine receptor/Ca2+ release channels are differentially expressed in rabbit brain. J Neurosci 14(8):4794–4805 (PubMed PMID: 8046450; PubMed Central PMCID: PMC6577160)

    Article  CAS  Google Scholar 

  55. Giannini G, Conti A, Mammarella S, Scrobogna M, Sorrentino V (1995) The ryanodine receptor/calcium channel genes are widely and differentially expressed in murine brain and peripheral tissues. J Cell Biol 128(5):893–904. https://doi.org/10.1083/jcb.128.5.893 (PubMed PMID: 7876312; PubMed Central PMCID: PMC2120385)

    Article  CAS  PubMed  Google Scholar 

  56. Imagawa T, Smith JS, Coronado R, Campbell KP (1987) Purified ryanodine receptor from skeletal muscle sarcoplasmic reticulum is the Ca2+-permeable pore of the calcium release channel. J Biol Chem 262(34):16636–16643 (PubMed PMID: 2445748)

    Article  CAS  Google Scholar 

  57. Takeshima H, Nishimura S, Matsumoto T, Ishida H, Kangawa K, Minamino N et al (1989) Primary structure and expression from complementary DNA of skeletal muscle ryanodine receptor. Nature 339(6224):439–445. https://doi.org/10.1038/339439a0 (PubMed PMID: 2725677)

    Article  CAS  PubMed  Google Scholar 

  58. Marks AR, Tempst P, Hwang KS, Taubman MB, Inui M, Chadwick C et al (1989) Molecular cloning and characterization of the ryanodine receptor/junctional channel complex cDNA from skeletal muscle sarcoplasmic reticulum. Proc Natl Acad Sci USA 86(22):8683–8687. https://doi.org/10.1073/pnas.86.22.8683 (PubMed PMID: 2813419; PubMed Central PMCID: PMC298352)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zorzato F, Fujii J, Otsu K, Phillips M, Green NM, Lai FA et al (1990) Molecular cloning of cDNA encoding human and rabbit forms of the Ca2+ release channel (ryanodine receptor) of skeletal muscle sarcoplasmic reticulum. J Biol Chem 265(4):2244–2256 (PubMed PMID: 2298749)

    Article  CAS  Google Scholar 

  60. Otsu K, Willard HF, Khanna VK, Zorzato F, Green NM, MacLennan DH (1990) Molecular cloning of cDNA encoding the Ca2+ release channel (ryanodine receptor) of rabbit cardiac muscle sarcoplasmic reticulum. J Biol Chem 265(23):13472–13483 (PubMed PMID: 2380170)

    Article  CAS  Google Scholar 

  61. Lanner JT, Georgiou DK, Joshi AD, Hamilton SL (2010) Ryanodine receptors: structure, expression, molecular details, and function in calcium release. Cold Spring Harb Perspect Biol 2(11):a003996. https://doi.org/10.1101/cshperspect.a003996 (Epub 2010/10/22. PubMed PMID: 20961976; PubMed Central PMCID: PMCPMC2964179)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Verkhratsky A, Shmigol A (1996) Calcium-induced calcium release in neurones. Cell Calcium 19(1):1–14. https://doi.org/10.1016/s0143-4160(96)90009-3 (Epub 1996/01/01. PubMed PMID: 8653752)

    Article  CAS  PubMed  Google Scholar 

  63. Meissner G (2017) The structural basis of ryanodine receptor ion channel function. J Gen Physiol 149(12):1065–1089. https://doi.org/10.1085/jgp.201711878 (Epub 2017/11/11. PubMed PMID: 29122978; PubMed Central PMCID: PMCPMC5715910)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bootman MD, Berridge MJ, Roderick HL (2002) Calcium signalling: more messengers, more channels, more complexity. Curr Biol 12(16):R563–R565. https://doi.org/10.1016/s0960-9822(02)01055-2 (Epub 2002/08/27. PubMed PMID: 12194839)

    Article  CAS  PubMed  Google Scholar 

  65. Murayama T, Ogawa Y (2004) RyR1 exhibits lower gain of CICR activity than RyR3 in the SR: evidence for selective stabilization of RyR1 channel. Am J Physiol Cell Physiol 287(1):C36-45. https://doi.org/10.1152/ajpcell.00395.2003 (Epub 2004/02/27. PubMed PMID: 14985235)

    Article  CAS  PubMed  Google Scholar 

  66. McGrew SG, Wolleben C, Siegl P, Inui M, Fleischer S (1989) Positive cooperativity of ryanodine binding to the calcium release channel of sarcoplasmic reticulum from heart and skeletal muscle. Biochemistry 28(4):1686–1691. https://doi.org/10.1021/bi00430a039 (PubMed PMID: 2541762)

    Article  CAS  PubMed  Google Scholar 

  67. Bezprozvanny I, Watras J, Ehrlich BE (1991) Bell-shaped calcium-response curves of Ins(1,4,5)P3- and calcium-gated channels from endoplasmic reticulum of cerebellum. Nature 351(6329):751–754. https://doi.org/10.1038/351751a0 (PubMed PMID: 1648178)

    Article  CAS  PubMed  Google Scholar 

  68. Dulhunty AF, Pouliquin P (2003) What we don’t know about the structure of ryanodine receptor calcium release channels. Clin Exp Pharmacol Physiol 30(10):713–723. https://doi.org/10.1046/j.1440-1681.2003.03904.x (Epub 2003/10/01. PubMed PMID: 14516409)

    Article  CAS  PubMed  Google Scholar 

  69. Xiao B, Masumiya H, Jiang D, Wang R, Sei Y, Zhang L et al (2002) Isoform-dependent formation of heteromeric Ca2+ release channels (ryanodine receptors). J Biol Chem 277(44):41778–41785. https://doi.org/10.1074/jbc.M208210200 (PubMed PMID: 12213830)

    Article  CAS  PubMed  Google Scholar 

  70. Furuichi T, Yoshikawa S, Miyawaki A, Wada K, Maeda N, Mikoshiba K (1989) Primary structure and functional expression of the inositol 1,4,5-trisphosphate-binding protein P400. Nature 342(6245):32–38. https://doi.org/10.1038/342032a0 (PubMed PMID: 2554142)

    Article  CAS  PubMed  Google Scholar 

  71. Maeda N, Niinobe M, Mikoshiba K (1990) A cerebellar Purkinje cell marker P400 protein is an inositol 1,4,5-trisphosphate (InsP3) receptor protein. Purification and characterization of InsP3 receptor complex. EMBO J 9(1):61–67 (PubMed PMID: 2153079; PubMed Central PMCID: PMC551630)

    Article  CAS  Google Scholar 

  72. Blondel O, Takeda J, Janssen H, Seino S, Bell GI (1993) Sequence and functional characterization of a third inositol trisphosphate receptor subtype, IP3R-3, expressed in pancreatic islets, kidney, gastrointestinal tract, and other tissues. J Biol Chem 268(15):11356–11363 (PubMed PMID: 8388391)

    Article  CAS  Google Scholar 

  73. Yamamoto-Hino M, Sugiyama T, Hikichi K, Mattei MG, Hasegawa K, Sekine S et al (1994) Cloning and characterization of human type 2 and type 3 inositol 1,4,5-trisphosphate receptors. Recept Channels 2(1):9–22 (Epub 1994/01/01. PubMed PMID: 8081734)

    CAS  PubMed  Google Scholar 

  74. Michell RH (1982) Inositol lipid metabolism in dividing and differentiating cells. Cell Calcium 3(4–5):429–440. https://doi.org/10.1016/0143-4160(82)90028-8 (Epub 1982/10/01. PubMed PMID: 6760977)

    Article  CAS  PubMed  Google Scholar 

  75. Berridge MJ (2016) The inositol trisphosphate/calcium signaling pathway in health and disease. Physiol Rev 96(4):1261–1296. https://doi.org/10.1152/physrev.00006.2016 (Epub 2016/08/12. PubMed PMID: 27512009)

    Article  CAS  PubMed  Google Scholar 

  76. Prole DL, Taylor CW (2016) Inositol 1,4,5-trisphosphate receptors and their protein partners as signalling hubs. J Physiol 594(11):2849–2866. https://doi.org/10.1113/JP271139 (Epub 2016/02/03. PubMed PMID: 26830355; PubMed Central PMCID: PMCPMC4887697)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Iwai M, Michikawa T, Bosanac I, Ikura M, Mikoshiba K (2007) Molecular basis of the isoform-specific ligand-binding affinity of inositol 1,4,5-trisphosphate receptors. J Biol Chem 282(17):12755–12764. https://doi.org/10.1074/jbc.M609833200 (PubMed PMID: 17327232)

    Article  CAS  PubMed  Google Scholar 

  78. Nerou EP, Riley AM, Potter BV, Taylor CW (2001) Selective recognition of inositol phosphates by subtypes of the inositol trisphosphate receptor. Biochem J 355(Pt 1):59–69. https://doi.org/10.1042/0264-6021:3550059 (PubMed PMID: 11256949; PubMed Central PMCID: PMC1221712)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Baker MR, Fan G, Seryshev AB, Agosto MA, Baker ML, Serysheva II (2021) Cryo-EM structure of type 1 IP3R channel in a lipid bilayer. Commun Biol 4(1):625. https://doi.org/10.1038/s42003-021-02156-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Betzenhauser MJ, Fike JL, Wagner LE 2nd, Yule DI (2009) Protein kinase A increases type-2 inositol 1,4,5-trisphosphate receptor activity by phosphorylation of serine 937. J Biol Chem 284(37):25116–25125. https://doi.org/10.1074/jbc.M109.010132 (PubMed PMID: 19608738; PubMed Central PMCID: PMC2757215)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Soulsby MD, Wojcikiewicz RJ (2007) Calcium mobilization via type III inositol 1,4,5-trisphosphate receptors is not altered by PKA-mediated phosphorylation of serines 916, 934, and 1832. Cell Calcium 42(3):261–270. https://doi.org/10.1016/j.ceca.2006.12.002 (PubMed PMID: 17257671; PubMed Central PMCID: PMC1975771)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Bimboese P, Gibson CJ, Schmidt S, Xiang W, Ehrlich BE (2011) Isoform-specific regulation of the inositol 1,4,5-trisphosphate receptor by O-linked glycosylation. J Biol Chem 286(18):15688–15697. https://doi.org/10.1074/jbc.M110.206482 (PubMed PMID: 21383013; PubMed Central PMCID: PMC3091177)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Rengifo J, Gibson CJ, Winkler E, Collin T, Ehrlich BE (2007) Regulation of the inositol 1,4,5-trisphosphate receptor type I by O-GlcNAc glycosylation. J Neurosci 27(50):13813–13821. https://doi.org/10.1523/JNEUROSCI.2069-07.2007 (PubMed PMID: 18077693; PubMed Central PMCID: PMC6673603)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Rizzuto R, Brini M, Murgia M, Pozzan T (1993) Microdomains with high Ca2+ close to IP3-sensitive channels that are sensed by neighboring mitochondria. Science 262(5134):744–747. https://doi.org/10.1126/science.8235595 (Epub 1993/10/29. PubMed PMID: 8235595)

    Article  CAS  PubMed  Google Scholar 

  85. De Stefani D, Rizzuto R, Pozzan T (2016) Enjoy the trip: calcium in mitochondria back and forth. Annu Rev Biochem 85:161–192. https://doi.org/10.1146/annurev-biochem-060614-034216 (PubMed PMID: 27145841)

    Article  CAS  PubMed  Google Scholar 

  86. La Rovere RM, Roest G, Bultynck G, Parys JB (2016) Intracellular Ca(2+) signaling and Ca(2+) microdomains in the control of cell survival, apoptosis and autophagy. Cell Calcium 60(2):74–87. https://doi.org/10.1016/j.ceca.2016.04.005 (Epub 2016/05/10. PubMed PMID: 27157108)

    Article  CAS  PubMed  Google Scholar 

  87. Mendes CC, Gomes DA, Thompson M, Souto NC, Goes TS, Goes AM et al (2005) The type III inositol 1,4,5-trisphosphate receptor preferentially transmits apoptotic Ca2+ signals into mitochondria. J Biol Chem 280(49):40892–40900. https://doi.org/10.1074/jbc.M506623200 (PubMed PMID: 16192275)

    Article  CAS  PubMed  Google Scholar 

  88. Mangla A, Guerra MT, Nathanson MH (2020) Type 3 inositol 1,4,5-trisphosphate receptor: A calcium channel for all seasons. Cell Calcium 85:102132. https://doi.org/10.1016/j.ceca.2019.102132 (PubMed PMID: 31790953; PubMed Central PMCID: PMC6917836)

    Article  CAS  PubMed  Google Scholar 

  89. Mignery GA, Sudhof TC, Takei K, De Camilli P (1989) Putative receptor for inositol 1,4,5-trisphosphate similar to ryanodine receptor. Nature 342(6246):192–195. https://doi.org/10.1038/342192a0 (PubMed PMID: 2554146)

    Article  CAS  PubMed  Google Scholar 

  90. Seo MD, Enomoto M, Ishiyama N, Stathopulos PB, Ikura M (2015) Structural insights into endoplasmic reticulum stored calcium regulation by inositol 1,4,5-trisphosphate and ryanodine receptors. Biochim Biophys Acta 1853(9):1980–1991. https://doi.org/10.1016/j.bbamcr.2014.11.023 (Epub 2014/12/03. PubMed PMID: 25461839)

    Article  CAS  PubMed  Google Scholar 

  91. Santulli G, Nakashima R, Yuan Q, Marks AR (2017) Intracellular calcium release channels: an update. J Physiol 595(10):3041–3051. https://doi.org/10.1113/jp272781 (Epub 2017/03/18. PubMed PMID: 28303572; PubMed Central PMCID: PMCPMC5430224)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Berridge MJ (2006) Calcium microdomains: organization and function. Cell Calcium 40(5–6):405–412. https://doi.org/10.1016/j.ceca.2006.09.002 (Epub 2006/10/13. PubMed PMID: 17030366)

    Article  CAS  PubMed  Google Scholar 

  93. McGeown JG (2004) Interactions between inositol 1,4,5-trisphosphate receptors and ryanodine receptors in smooth muscle: one store or two? Cell Calcium 35(6):613–619. https://doi.org/10.1016/j.ceca.2004.01.016 (Epub 2004/04/28. PubMed PMID: 15110151)

    Article  CAS  PubMed  Google Scholar 

  94. Niggli E (1999) Localized intracellular calcium signaling in muscle: calcium sparks and calcium quarks. Annu Rev Physiol 61:311–335. https://doi.org/10.1146/annurev.physiol.61.1.311 (Epub 1999/04/01. PubMed PMID: 10099691)

    Article  CAS  PubMed  Google Scholar 

  95. Manita S, Ross WN (2009) Synaptic activation and membrane potential changes modulate the frequency of spontaneous elementary Ca2+ release events in the dendrites of pyramidal neurons. J Neurosci 29(24):7833–7845. https://doi.org/10.1523/JNEUROSCI.0573-09.2009 (Epub 2009/06/19. PubMed PMID: 19535595; PubMed Central PMCID: PMCPMC2756180)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Miyazaki K, Ross WN (2013) Ca2+ sparks and puffs are generated and interact in rat hippocampal CA1 pyramidal neuron dendrites. J Neurosci 33(45):17777–17788. https://doi.org/10.1523/JNEUROSCI.2735-13.2013 (Epub 2013/11/08. PubMed PMID: 24198368; PubMed Central PMCID: PMCPMC3818551)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. McDaid J, Mustaly-Kalimi S, Stutzmann GE (2020) Ca(2+) dyshomeostasis disrupts neuronal and synaptic function in Alzheimer’s disease. Cells. https://doi.org/10.3390/cells9122655 (Epub 2020/12/17. PubMed PMID: 33321866; PubMed Central PMCID: PMCPMC7763805)

    Article  PubMed  PubMed Central  Google Scholar 

  98. Grosskreutz J, Van Den Bosch L, Keller BU (2010) Calcium dysregulation in amyotrophic lateral sclerosis. Cell Calcium 47(2):165–174. https://doi.org/10.1016/j.ceca.2009.12.002 (Epub 2010/02/02. PubMed PMID: 20116097)

    Article  CAS  PubMed  Google Scholar 

  99. Naia L, Ferreira IL, Ferreiro E, Rego AC (2017) Mitochondrial Ca(2+) handling in Huntington’s and Alzheimer’s diseases—role of ER-mitochondria crosstalk. Biochem Biophys Res Commun 483(4):1069–1077. https://doi.org/10.1016/j.bbrc.2016.07.122 (Epub 2016/08/04. PubMed PMID: 27485547)

    Article  CAS  PubMed  Google Scholar 

  100. Orem BC, Pelisch N, Williams J, Nally JM, Stirling DP (2017) Intracellular calcium release through IP(3)R or RyR contributes to secondary axonal degeneration. Neurobiol Dis 106:235–243. https://doi.org/10.1016/j.nbd.2017.07.011 (Epub 2017/07/16. PubMed PMID: 28709993)

    Article  CAS  PubMed  Google Scholar 

  101. Zhao H, Tong G, Liu J, Wang J, Zhang H, Bai J et al (2019) IP3R and RyR channels are involved in traffic-related PM(2.5)-induced disorders of calcium homeostasis. Toxicol Ind Health 35(5):339–348. https://doi.org/10.1177/0748233719843763 (Epub 2019/04/27. PubMed PMID: 31023176)

    Article  CAS  PubMed  Google Scholar 

  102. Hetz C, Zhang K, Kaufman RJ (2020) Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol 21(8):421–438. https://doi.org/10.1038/s41580-020-0250-z (Epub 2020/05/28. PubMed PMID: 32457508)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Ghemrawi R, Khair M (2020) Endoplasmic reticulum stress and unfolded protein response in neurodegenerative diseases. Int J Mol Sci. https://doi.org/10.3390/ijms21176127 (Epub 2020/08/29. PubMed PMID: 32854418; PubMed Central PMCID: PMCPMC7503386)

    Article  PubMed  PubMed Central  Google Scholar 

  104. Stefani IC, Wright D, Polizzi KM, Kontoravdi C (2012) The role of ER stress-induced apoptosis in neurodegeneration. Curr Alzheimer Res 9(3):373–387. https://doi.org/10.2174/156720512800107618 (Epub 2012/02/04. PubMed PMID: 22299619)

    Article  CAS  PubMed  Google Scholar 

  105. Hetz C, Saxena S (2017) ER stress and the unfolded protein response in neurodegeneration. Nat Rev Neurol 13(8):477–491. https://doi.org/10.1038/nrneurol.2017.99 (Epub 2017/07/22. PubMed PMID: 28731040)

    Article  CAS  PubMed  Google Scholar 

  106. Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334(6059):1081–1086. https://doi.org/10.1126/science.1209038 (Epub 2011/11/26. PubMed PMID: 22116877)

    Article  CAS  PubMed  Google Scholar 

  107. Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP (2007) MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell 27(1):91–105. https://doi.org/10.1016/j.molcel.2007.06.017 (Epub 2007/07/07. PubMed PMID: 17612493)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Agarwal V, Bell GW, Nam JW, Bartel DP (2015) Predicting effective microRNA target sites in mammalian mRNAs. Elife. https://doi.org/10.7554/eLife.05005 (Epub 2015/08/13. PubMed PMID: 26267216; PubMed Central PMCID: PMCPMC4532895)

    Article  PubMed  PubMed Central  Google Scholar 

  109. Kiriakidou M, Nelson PT, Kouranov A, Fitziev P, Bouyioukos C, Mourelatos Z et al (2004) A combined computational-experimental approach predicts human microRNA targets. Genes Dev 18(10):1165–1178. https://doi.org/10.1101/gad.1184704 (Epub 2004/05/08. PubMed PMID: 15131085; PubMed Central PMCID: PMC415641)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Paraskevopoulou MD, Georgakilas G, Kostoulas N, Vlachos IS, Vergoulis T, Reczko M et al (2013) DIANA-microT web server v5.0: service integration into miRNA functional analysis workflows. Nucleic Acids Res. 2013;41(Web Server issue):W169–W173. https://doi.org/10.1093/nar/gkt393(PubMed PMID: 23680784; PubMed Central PMCID: PMC3692048)

  111. Wong N, Wang X (2015) miRDB: an online resource for microRNA target prediction and functional annotations. Nucleic Acids Res 43(Database issue):D146–D152. https://doi.org/10.1093/nar/gku1104(PubMed PMID: 25378301; PubMed Central PMCID: PMC4383922)

  112. Fehlmann T, Ludwig N, Backes C, Meese E, Keller A (2016) Distribution of microRNA biomarker candidates in solid tissues and body fluids. RNA Biol 13(11):1084–1088. https://doi.org/10.1080/15476286.2016.1234658 (PubMed PMID: 27687236; PubMed Central PMCID: PMC5100342)

    Article  PubMed  PubMed Central  Google Scholar 

  113. Guo Z, Maki M, Ding R, Yang Y, Zhang B, Xiong L (2014) Genome-wide survey of tissue-specific microRNA and transcription factor regulatory networks in 12 tissues. Sci Rep 4:5150. https://doi.org/10.1038/srep05150 (Epub 2014/06/04. PubMed PMID: 24889152; PubMed Central PMCID: PMCPMC5381490)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Ludwig N, Leidinger P, Becker K, Backes C, Fehlmann T, Pallasch C et al (2016) Distribution of miRNA expression across human tissues. Nucleic Acids Res 44(8):3865–3877. https://doi.org/10.1093/nar/gkw116 (Epub 2016/02/28. PubMed PMID: 26921406; PubMed Central PMCID: PMCPMC4856985)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Kong H, Jones PP, Koop A, Zhang L, Duff HJ, Chen SR (2008) Caffeine induces Ca2+ release by reducing the threshold for luminal Ca2+ activation of the ryanodine receptor. Biochem J 414(3):441–452. https://doi.org/10.1042/BJ20080489 (Epub 2008/06/04. PubMed PMID: 18518861; PubMed Central PMCID: PMCPMC2747660)

    Article  CAS  PubMed  Google Scholar 

  116. McPherson PS, Kim YK, Valdivia H, Knudson CM, Takekura H, Franzini-Armstrong C et al (1991) The brain ryanodine receptor: a caffeine-sensitive calcium release channel. Neuron 7(1):17–25. https://doi.org/10.1016/0896-6273(91)90070-g (Epub 1991/07/01. PubMed PMID: 1648939)

    Article  CAS  PubMed  Google Scholar 

  117. Guerreiro S, Marien M, Michel PP (2011) Methylxanthines and ryanodine receptor channels. Handb Exp Pharmacol 200:135–150. https://doi.org/10.1007/978-3-642-13443-2_5 (Epub 2010/09/23. PubMed PMID: 20859795)

    Article  CAS  Google Scholar 

  118. Fisher SK, Snider RM (1987) Differential receptor occupancy requirements for muscarinic cholinergic stimulation of inositol lipid hydrolysis in brain and in neuroblastomas. Mol Pharmacol 32(1):81–90 (Epub 1987/07/01. PubMed PMID: 3600615)

    CAS  PubMed  Google Scholar 

  119. Baird JG, Lambert DG, McBain J, Nahorski SR (1989) Muscarinic receptors coupled to phosphoinositide hydrolysis and elevated cytosolic calcium in a human neuroblastoma cell line SK-N-SH. Br J Pharmacol 98(4):1328–1334. https://doi.org/10.1111/j.1476-5381.1989.tb12681.x (Epub 1989/12/01. PubMed PMID: 2558760; PubMed Central PMCID: PMCPMC1854815)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Lambert DG, Nahorski SR (1990) Muscarinic-receptor-mediated changes in intracellular Ca2+ and inositol 1,4,5-trisphosphate mass in a human neuroblastoma cell line, SH-SY5Y. Biochem J 265(2):555–562. https://doi.org/10.1042/bj2650555 (Epub 1990/01/15. PubMed PMID: 2302186; PubMed Central PMCID: PMCPMC1136919)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. White C, McGeown JG (2002) Carbachol triggers RyR-dependent Ca(2+) release via activation of IP(3) receptors in isolated rat gastric myocytes. J Physiol 542(Pt 3):725–733. https://doi.org/10.1113/jphysiol.2002.020131 (Epub 2002/08/03. PubMed PMID: 12154174; PubMed Central PMCID: PMCPMC2290441)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Thastrup O, Cullen PJ, Drobak BK, Hanley MR, Dawson AP (1990) Thapsigargin, a tumor promoter, discharges intracellular Ca2+ stores by specific inhibition of the endoplasmic reticulum Ca2(+)-ATPase. Proc Natl Acad Sci USA 87(7):2466–2470. https://doi.org/10.1073/pnas.87.7.2466 (Epub 1990/04/01. PubMed PMID: 2138778; PubMed Central PMCID: PMCPMC53710)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Treiman M, Caspersen C, Christensen SB (1998) A tool coming of age: thapsigargin as an inhibitor of sarco-endoplasmic reticulum Ca(2+)-ATPases. Trends Pharmacol Sci 19(4):131–135. https://doi.org/10.1016/s0165-6147(98)01184-5 (Epub 1998/06/05. PubMed PMID: 9612087)

    Article  CAS  PubMed  Google Scholar 

  124. Foufelle F, Fromenty B (2016) Role of endoplasmic reticulum stress in drug-induced toxicity. Pharmacol Res Perspect 4(1):e00211. https://doi.org/10.1002/prp2.211 (Epub 2016/03/16. PubMed PMID: 26977301; PubMed Central PMCID: PMCPMC4777263)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Yoo J, Mashalidis EH, Kuk ACY, Yamamoto K, Kaeser B, Ichikawa S et al (2018) GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation. Nat Struct Mol Biol 25(3):217–224. https://doi.org/10.1038/s41594-018-0031-y (Epub 2018/02/21. PubMed PMID: 29459785; PubMed Central PMCID: PMCPMC5840018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Wang H, Wang X, Ke ZJ, Comer AL, Xu M, Frank JA et al (2015) Tunicamycin-induced unfolded protein response in the developing mouse brain. Toxicol Appl Pharmacol 283(3):157–167. https://doi.org/10.1016/j.taap.2014.12.019 (Epub 2015/01/27. PubMed PMID: 25620058; PubMed Central PMCID: PMCPMC4361256)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Chiang DY, Kongchan N, Beavers DL, Alsina KM, Voigt N, Neilson JR et al (2014) Loss of microRNA-106b-25 cluster promotes atrial fibrillation by enhancing ryanodine receptor type-2 expression and calcium release. Circ Arrhythm Electrophysiol 7(6):1214–1222. https://doi.org/10.1161/CIRCEP.114.001973 (Epub 2014/11/13. PubMed PMID: 25389315; PubMed Central PMCID: PMCPMC4270890)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Zhang L, Liu Y, Song F, Zheng H, Hu L, Lu H et al (2011) Functional SNP in the microRNA-367 binding site in the 3’UTR of the calcium channel ryanodine receptor gene 3 (RYR3) affects breast cancer risk and calcification. Proc Natl Acad Sci USA 108(33):13653–13658. https://doi.org/10.1073/pnas.1103360108 (Epub 2011/08/04. PubMed PMID: 21810988; PubMed Central PMCID: PMCPMC3158174)

    Article  PubMed  PubMed Central  Google Scholar 

  129. Wahlquist C, Jeong D, Rojas-Munoz A, Kho C, Lee A, Mitsuyama S et al (2014) Inhibition of miR-25 improves cardiac contractility in the failing heart. Nature 508(7497):531–535. https://doi.org/10.1038/nature13073 (Epub 2014/03/29. PubMed PMID: 24670661; PubMed Central PMCID: PMCPMC4131725)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Gabani M, Liu J, Ait-Aissa K, Koval O, Kim YR, Castaneda D et al (2019) MiR-204 regulates type 1 IP3R to control vascular smooth muscle cell contractility and blood pressure. Cell Calcium 80:18–24. https://doi.org/10.1016/j.ceca.2019.03.006 (Epub 2019/03/30. PubMed PMID: 30925290; PubMed Central PMCID: PMCPMC6767906)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Diener C, Hart M, Alansary D, Poth V, Walch-Ruckheim B, Menegatti J et al (2018) Modulation of intracellular calcium signaling by microRNA-34a-5p. Cell Death Dis 9(10):1008. https://doi.org/10.1038/s41419-018-1050-7 (Epub 2018/09/29. PubMed PMID: 30262862; PubMed Central PMCID: PMCPMC6160487)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Drawnel FM, Wachten D, Molkentin JD, Maillet M, Aronsen JM, Swift F et al (2012) Mutual antagonism between IP(3)RII and miRNA-133a regulates calcium signals and cardiac hypertrophy. J Cell Biol 199(5):783–798. https://doi.org/10.1083/jcb.201111095 (Epub 2012/11/21. PubMed PMID: 23166348; PubMed Central PMCID: PMCPMC3514786)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Ananthanarayanan M, Banales JM, Guerra MT, Spirli C, Munoz-Garrido P, Mitchell-Richards K et al (2015) Post-translational regulation of the type III inositol 1,4,5-trisphosphate receptor by miRNA-506. J Biol Chem 290(1):184–196. https://doi.org/10.1074/jbc.M114.587030 (Epub 2014/11/08. PubMed PMID: 25378392; PubMed Central PMCID: PMCPMC4281721)

    Article  CAS  PubMed  Google Scholar 

  134. Baker KD, Edwards TM, Rickard NS (2013) The role of intracellular calcium stores in synaptic plasticity and memory consolidation. Neurosci Biobehav Rev 37(7):1211–1239. https://doi.org/10.1016/j.neubiorev.2013.04.011 (Epub 2013/05/04. PubMed PMID: 23639769)

    Article  CAS  PubMed  Google Scholar 

  135. Paschou M, Doxakis E (2012) Neurofibromin 1 Is a miRNA Target in Neurons. PLoS ONE 7(10):e46773. https://doi.org/10.1371/journal.pone.0046773 (PubMed PMID: 23056445; PubMed Central PMCID: PMC3462785)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Paschou M, Paraskevopoulou MD, Vlachos IS, Koukouraki P, Hatzigeorgiou AG, Doxakis E (2012) miRNA regulons associated with synaptic function. PLoS ONE 7(10):e46189. https://doi.org/10.1371/journal.pone.0046189 (PubMed PMID: 23071543; PubMed Central PMCID: PMC3468272)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Paschou M, Doxakis E (2012) Neurofibromin 1 is a miRNA target in neurons. PLoS ONE. https://doi.org/10.1371/journal.pone.0046773

    Article  PubMed  PubMed Central  Google Scholar 

  138. Banerjee S, Hasan G (2005) The InsP3 receptor: its role in neuronal physiology and neurodegeneration. BioEssays 27(10):1035–1047. https://doi.org/10.1002/bies.20298 (Epub 2005/09/16. PubMed PMID: 16163728)

    Article  CAS  PubMed  Google Scholar 

  139. Del Prete D, Checler F, Chami M (2014) Ryanodine receptors: physiological function and deregulation in Alzheimer disease. Mol Neurodegener 9:21. https://doi.org/10.1186/1750-1326-9-21 (Epub 2014/06/07. PubMed PMID: 24902695; PubMed Central PMCID: PMCPMC4063224)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Thibault O, Porter NM, Chen KC, Blalock EM, Kaminker PG, Clodfelter GV et al (1998) Calcium dysregulation in neuronal aging and Alzheimer’s disease: history and new directions. Cell Calcium 24(5–6):417–433. https://doi.org/10.1016/s0143-4160(98)90064-1 (Epub 1999/03/26. PubMed PMID: 10091010)

    Article  CAS  PubMed  Google Scholar 

  141. O’Neill C, Cowburn RF, Bonkale WL, Ohm TG, Fastbom J, Carmody M et al (2001) Dysfunctional intracellular calcium homoeostasis: a central cause of neurodegeneration in Alzheimer’s disease. Biochem Soc Symp 67:177–194. https://doi.org/10.1042/bss0670177 (Epub 2001/07/13. PubMed PMID: 11447834)

    Article  CAS  Google Scholar 

  142. Gant JC, Sama MM, Landfield PW, Thibault O (2006) Early and simultaneous emergence of multiple hippocampal biomarkers of aging is mediated by Ca2+-induced Ca2+ release. J Neurosci 26(13):3482–3490. https://doi.org/10.1523/JNEUROSCI.4171-05.2006 (Epub 2006/03/31. PubMed PMID: 16571755; PubMed Central PMCID: PMCPMC6673869)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Oules B, Del Prete D, Greco B, Zhang X, Lauritzen I, Sevalle J et al (2012) Ryanodine receptor blockade reduces amyloid-beta load and memory impairments in Tg2576 mouse model of Alzheimer disease. J Neurosci 32(34):11820–11834. https://doi.org/10.1523/JNEUROSCI.0875-12.2012 (Epub 2012/08/24. PubMed PMID: 22915123; PubMed Central PMCID: PMCPMC3458216)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Ruiz A, Matute C, Alberdi E (2009) Endoplasmic reticulum Ca(2+) release through ryanodine and IP(3) receptors contributes to neuronal excitotoxicity. Cell Calcium 46(4):273–281. https://doi.org/10.1016/j.ceca.2009.08.005 (Epub 2009/09/15. PubMed PMID: 19747726)

    Article  CAS  PubMed  Google Scholar 

  145. Zhao S, Deng Y, Liu Y, Chen X, Yang G, Mu Y et al (2013) MicroRNA-153 is tumor suppressive in glioblastoma stem cells. Mol Biol Rep 40(4):2789–2798. https://doi.org/10.1007/s11033-012-2278-4 (Epub 2013/02/12. PubMed PMID: 23397238)

    Article  CAS  PubMed  Google Scholar 

  146. Fragkouli A, Doxakis E (2014) miR-7 and miR-153 protect neurons against MPP(+)-induced cell death via upregulation of mTOR pathway. Front Cell Neurosci 8:182. https://doi.org/10.3389/fncel.2014.00182 (Epub 2014/07/30. PubMed PMID: 25071443; PubMed Central PMCID: PMCPMC4080263)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Tsai PC, Bake S, Balaraman S, Rawlings J, Holgate RR, Dubois D et al (2014) MiR-153 targets the nuclear factor-1 family and protects against teratogenic effects of ethanol exposure in fetal neural stem cells. Biology open. 3(8):741–758. https://doi.org/10.1242/bio.20147765 (Epub 2014/07/27. PubMed PMID: 25063196; PubMed Central PMCID: PMCPMC4133727)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Nolan JC, Salvucci M, Carberry S, Barat A, Segura MF, Fenn J et al (2020) A context-dependent role for MiR-124-3p on cell phenotype, viability and chemosensitivity in neuroblastoma in vitro. Front Cell Dev Biol 8:559553. https://doi.org/10.3389/fcell.2020.559553 (Epub 2020/12/18. PubMed PMID: 33330445; PubMed Central PMCID: PMCPMC7714770)

    Article  PubMed  PubMed Central  Google Scholar 

  149. Ferreiro E, Oliveira CR, Pereira C (2004) Involvement of endoplasmic reticulum Ca2+ release through ryanodine and inositol 1,4,5-triphosphate receptors in the neurotoxic effects induced by the amyloid-beta peptide. J Neurosci Res 76(6):872–880. https://doi.org/10.1002/jnr.20135 (Epub 2004/05/26. PubMed PMID: 15160398)

    Article  CAS  PubMed  Google Scholar 

  150. Popescu BO, Oprica M, Sajin M, Stanciu CL, Bajenaru O, Predescu A et al (2002) Dantrolene protects neurons against kainic acid induced apoptosis in vitro and in vivo. J Cell Mol Med 6(4):555–569. https://doi.org/10.1111/j.1582-4934.2002.tb00454.x (Epub 2003/03/04. PubMed PMID: 12611640; PubMed Central PMCID: PMCPMC6741407)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Ruiz A, Matute C, Alberdi E (2010) Intracellular Ca2+ release through ryanodine receptors contributes to AMPA receptor-mediated mitochondrial dysfunction and ER stress in oligodendrocytes. Cell Death Dis 1:e54. https://doi.org/10.1038/cddis.2010.31 (Epub 2011/03/03. PubMed PMID: 21364659; PubMed Central PMCID: PMCPMC3032558)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Panganiban RA, Park H-R, Sun M, Shumyatcher M, Himes BE, Lu Q (2019) Genome-wide CRISPR screen identifies suppressors of endoplasmic reticulum stress-induced apoptosis. Proc Natl Acad Sci 116(27):13384. https://doi.org/10.1073/pnas.1906275116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Ding C, Dou M, Wang Y, Li Y, Wang Y, Zheng J et al (2020) miR-124/IRE-1α affects renal ischemia/reperfusion injury by regulating endoplasmic reticulum stress in renal tubular epithelial cells. Acta Biochim Biophys Sin 52(2):160–167. https://doi.org/10.1093/abbs/gmz150

    Article  CAS  PubMed  Google Scholar 

  154. Park H-R, Sun R, Panganiban RA, Christiani DC, Lu Q (2020) MicroRNA-124 reduces arsenic-induced endoplasmic reticulum stress and neurotoxicity and is linked with neurodevelopment in children. Sci Rep 10(1):5934. https://doi.org/10.1038/s41598-020-62594-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Liang H, Xiao J, Zhou Z, Wu J, Ge F, Li Z et al (2018) Hypoxia induces miR-153 through the IRE1α-XBP1 pathway to fine tune the HIF1α/VEGFA axis in breast cancer angiogenesis. Oncogene 37(15):1961–1975. https://doi.org/10.1038/s41388-017-0089-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Atlante A, Calissano P, Bobba A, Giannattasio S, Marra E, Passarella S (2001) Glutamate neurotoxicity, oxidative stress and mitochondria. FEBS Lett 497(1):1–5. https://doi.org/10.1016/s0014-5793(01)02437-1 (Epub 2001/05/30. PubMed PMID: 11376653)

    Article  CAS  PubMed  Google Scholar 

  157. Subramaniam SR, Chesselet MF (2013) Mitochondrial dysfunction and oxidative stress in Parkinson’s disease. Prog Neurobiol 106–107:17–32. https://doi.org/10.1016/j.pneurobio.2013.04.004 (Epub 2013/05/07. PubMed PMID: 23643800; PubMed Central PMCID: PMCPMC3742021)

    Article  CAS  PubMed  Google Scholar 

  158. Karagas NE, Venkatachalam K (2019) Roles for the endoplasmic reticulum in regulation of neuronal calcium homeostasis. Cells. https://doi.org/10.3390/cells8101232 (Epub 2019/10/30. PubMed PMID: 31658749; PubMed Central PMCID: PMCPMC6829861)

    Article  PubMed  PubMed Central  Google Scholar 

  159. Haraguchi T, Ozaki Y, Iba H (2009) Vectors expressing efficient RNA decoys achieve the long-term suppression of specific microRNA activity in mammalian cells. Nucleic Acids Res 37(6):e43. https://doi.org/10.1093/nar/gkp040 (PubMed PMID: 19223327; PubMed Central PMCID: PMC2665227)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Bak RO, Hollensen AK, Primo MN, Sorensen CD, Mikkelsen JG (2013) Potent microRNA suppression by RNA Pol II-transcribed “Tough Decoy” inhibitors. RNA 19(2):280–293. https://doi.org/10.1261/rna.034850.112 (PubMed PMID: 23249752; PubMed Central PMCID: PMC3543086)

    Article  PubMed  PubMed Central  Google Scholar 

  161. Ravanidis S, Bougea A, Papagiannakis N, Maniati M, Koros C, Simitsi AM et al (2020) Circulating brain-enriched MicroRNAs for detection and discrimination of idiopathic and genetic Parkinson’s disease. Mov Disord 35(3):457–467. https://doi.org/10.1002/mds.27928 (PubMed PMID: 31799764)

    Article  CAS  PubMed  Google Scholar 

  162. Gee KR, Brown KA, Chen WN, Bishop-Stewart J, Gray D, Johnson I (2000) Chemical and physiological characterization of fluo-4 Ca(2+)-indicator dyes. Cell Calcium 27(2):97–106. https://doi.org/10.1054/ceca.1999.0095 (Epub 2000/04/11. PubMed PMID: 10756976)

    Article  CAS  PubMed  Google Scholar 

  163. Grynkiewicz G, Poenie M, Tsien RY (1985) A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 260(6):3440–3450 (Epub 1985/03/25. PubMed PMID: 3838314)

    Article  CAS  Google Scholar 

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Funding

This work was supported by grants from the Greek General Secretariat for Research and Technology (GSRT) to ED (MIS380201, 12RUS-11-65), SGD (ARISTEIA II 4475), and PP (ARISTEIA I 1507). The funders had no role in the study design, the collection, data analysis, or the manuscript's preparation.

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  1. Michael Zachariadis

    Present address: Material and Chemical Characterization Facility (MC2), Faculty of Science, University of Bath, Claverton Down, Bath, BA2 7AY, UK

Authors and Affiliations

  1. Center for Basic Research, Biomedical Research Foundation, Academy of Athens (BRFAA), Soranou Efesiou 4, 11527, Athens, Greece

    Maria Paschou, Chrysanthi Charalampous & Epaminondas Doxakis

  2. Department of Biology, National and Kapodistrian University of Athens (NKUA), Panepistimiopolis, 15784, Athens, Greece

    Maria Paschou, Panagiota Papazafiri, Michael Zachariadis & Skarlatos G. Dedos

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  1. Maria Paschou
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Contributions

Conceived the study: ED. Designed and optimized protocols: ED, MP, and PP. Prepared plasmid constructs: ED, MP, and CC. Performed tissue culture and molecular biology experiments: MP and CC. Performed Ca2+ imaging experiments: MP, PP, MZ, and CC. Analyzed data: MP, PP, ED, MZ, and SGD. Wrote the manuscript: ED and MP. All authors read, edited, and approved the final manuscript.

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Correspondence to Skarlatos G. Dedos or Epaminondas Doxakis.

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18_2022_4398_MOESM1_ESM.tif

Figure S1. miRNA and RyR1-3, IP3R1-3 mRNA expression in human tissues, primary cortical neurons and SK-N-SH cells. A Quantification of endogenous RNA expression levels (log10) of RyR1-3 and IP3R1-3 mRNAs, miR-96, miR-124, miR-153, and miR-182 in different human tissues measured by RT-qPCR using GAPDH and U6 mRNAs as reference controls. Data show the mean ± SD from two technical replicates. B Boxplot of ΔCT values (CT of mRNA or miRNA minus CT of reference gene mRNA) of RyR1-3, IP3R1-3 mRNA, miR-96, miR-124, miR-153, and miR-182 endogenous expression in primary cortical neurons measured by RT-qPCR. GAPDH mRNA was used as an internal reference control. The boxes indicate the interquartile range (IQR), the whiskers show the range of values within 1.5 x IQR, and the horizontal line indicates the median. Dots represent individual ΔCT values obtained from two biological replicates (two technical replicates) per RNA group. C Boxplot of ΔCT values of miR-96, miR-124, miR-153, and miR-182 endogenous expression in SK-N-SH cells measured by RT-qPCR, using GAPDH mRNA as an internal reference control. Dots represent individual ΔCT values obtained from ten biological replicates per miRNA group. ( D–G) Relative miRNA expression levels in SK-N-SH cells following transfection with pri-miR-96, pri-miR-124, pri-miR-153, and pri-miR-182 pcDNA6.2-GW/EmGFP-miR expression vectors. miRNA levels were quantified by RT-qPCR 48 h later, using GAPDH and U6 mRNAs for normalization. Data show the mean ± SD from three biological replicates. Statistical significance was evaluated by two-tailed Student’s t test for paired samples, compared to the control group (*, p<0.05; **, p<0.01; ***, p<0.001). (TIF 2750 KB)

18_2022_4398_MOESM2_ESM.tif

Figure S2. Design of TuD constructs. A schematic of the TuD-124 (A) and TuD-153 (B) RNA structure and sequence. TuD inhibitors form a hairpin-shaped RNA structure that exposes two opposing miRNA-binding sites (depicted in red color). Endogenous miR-124-3p and miR-153-3p (depicted in green color) bind with imperfect complementarity to these sites, preventing them from binding to target genes. (TIF 2174 KB)

18_2022_4398_MOESM3_ESM.tif

Figure S3. miR-124 and miR-153 reduce RyR1-3 and IP3R3 protein levels in C2C12 cells. Representative immunoblot images of pan-RyR (A) or IP3R3 (B) protein levels in C2C12 cells transfected with miR-124 or miR-153 plasmids for 48 h. β-Adaptin and α-Tubulin were used as internal normalization controls, obtained from different gels with identical protein loading. The molecular weights of the proteins, as indicated by the antibody manufacturers, are depicted on the left of each blot image. Pixel intensity analysis revealed that pan-RyR and IP3R3 protein levels were significantly lower upon miR-124 or miR-153 overexpression than miR-SC control. Data show the mean ± SD from four independent biological replicates. Statistical significance was evaluated by one-way ANOVA followed by Dunnett’s multiple comparison test for repeated measurements (pan-RyR) or two-tailed Student’s t test for paired samples (IP3R3), compared to the control group (*, p<0.05; ***, p<0.001). (TIF 1443 KB)

18_2022_4398_MOESM4_ESM.tif

Figure S4. Effects of different concentrations of Ca2+ modulators on Ca2+ mobilization in SK-N-SH cells. Representative dose-dependent curves of Ca2+ amplitude (expressed as ΔF/F0) in response to (A) CAFF (15, 30, 60 mM), (B) CCh (0.5, 1, 2 mM), and (C) Tg (0.5, 1, 2 μM). Untransfected SK-N-SH cells were loaded with Fluo-4, and differences in the fluorescence intensity were monitored over time, before and after stimulation with the reagents, in extracellular Ca2+ free conditions. ΔF/F0 represents changes in the fluorescence intensity over baseline levels over time. Arrows indicate the timing of the addition of reagents. Black curves depict the response to the concentration of each reagent that was chosen for further experiments (CAFF, 30 mM; CCh, 1 mM; Tg, 2 μM). (TIF 770 KB)

18_2022_4398_MOESM5_ESM.tif

Figure S5. Tunicamycin induces ER stress in a dose-dependent manner. A Representative immunoblot images of untransfected SK-N-SH cells treated with increasing concentrations of Tm (0.5, 1, 2, 5, 10 μg/ml) for 24 h. Protein levels of p-eIF2α, ATF4, IRE1α, ATF6, XBP1s, and GRP78 were measured with total eIF2α, β-Adaptin, α-Tubulin, or GAPDH being used as loading controls for normalization. The molecular weights of the proteins, as indicated by the antibody manufacturers, are depicted on the left of each blot image. The red dashed box highlights the results obtained with 2 μg/ml Tm, chosen for further experiments. (TIF 2816 KB)

18_2022_4398_MOESM6_ESM.tif

Figure S6. Uncropped Western blot images used in Fig 4, Fig 8, Fig 9, Fig S3, and Fig S5. Dashed boxes contain the protein of interest and loading controls (β-Adaptin, α-Tubulin, GAPDH) run in the same gel. Positions of the molecular weight markers and their sizes are depicted on the left of each blot image and the molecular weight of each protein, as indicated by the antibody manufacturers, is displayed on the right. (TIF 13000 KB)

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Paschou, M., Papazafiri, P., Charalampous, C. et al. Neuronal microRNAs safeguard ER Ca2+ homeostasis and attenuate the unfolded protein response upon stress. Cell. Mol. Life Sci. 79, 373 (2022). https://doi.org/10.1007/s00018-022-04398-9

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