Skip to main content

Presenilin-1 Delta E9 Mutant Induces STIM1-Driven Store-Operated Calcium Channel Hyperactivation in Hippocampal Neurons

Molecular Neurobiology volume 55, pages 4667–4680 (2018)Cite this article

Abstract

Presenilins regulate calcium homeostasis in the endoplasmic reticulum, and dysregulation of intracellular calcium has been implicated in the pathogenesis of Alzheimer disease. Elevated presenilin-1 (PS1) holoprotein levels have been detected in postmortem brains of patients carrying familial Alzheimer disease (FAD) PS1 mutations. This study examines the effect of the FAD presenilin mutant that lacks the ninth exon (PS1 ∆E9) and does not undergo endoproteolysis on store-operated calcium (SOC) entry. Significant enhancement of SOC channel activation was detected by electrophysiological measurements in hippocampal neurons with PS1 ∆E9 mutant expression. Here, we show that (i) the hyperactivation of SOC channels is mediated by the STIM1 sensor and can be attenuated by STIM1 knockdown or 2-aminoethoxydiphenyl borate application, (ii) the STIM2 is not involved in pathological changes of SOC entry, (iii) the pathological SOC entry demonstrates properties of both TRPC and Orai subunit composition, and (iiii) transgenic Drosophila flies with PS1 ∆E9 expression in the cholinergic neuron system show short-term memory loss, which can be abolished by 2-aminoethoxydiphenyl borate feeding.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. Bekris LM, Yu CE, Bird TD, Tsuang DW (2010) Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol 23:213–227

    Article  PubMed  PubMed Central  Google Scholar 

  2. Beher D, Wrigley JD, Nadin A, Evin G, Masters CL, Harrison T, Castro JL, Shearman MS (2001) Pharmacological knock-down of the presenilin 1 heterodimer by a novel gamma-secretase inhibitor: implications for presenilin biology. J Biol Chem 276:45394–453402

    Article  CAS  PubMed  Google Scholar 

  3. Honarnejad K, Jung CK, Lammich S, Arzberger T, Kretzschmar H, Herms J (2013) Involvement of presenilin holoprotein upregulation in calcium dyshomeostasis of Alzheimer’s disease. J Cell Mol Med 17:293–302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ryazantseva M, Skobeleva K, Kaznacheyeva E (2013) Familial Alzheimer’s disease-linked presenilin-1 mutation M146V affects store-operated calcium entry: does gain look like loss? Biochimie 95:1506–1509

    Article  CAS  PubMed  Google Scholar 

  5. Sepulveda-Falla D, Barrera-Ocampo A, Hagel C, Korwitz A, Vinueza-Veloz MF, Zhou K, Schonewille M, Zhou H et al (2014) Familial Alzheimer’s disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis. J Clin Invest 124:1552–1567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ryazantseva M, Skobeleva K, Glushankova L, Kaznacheyeva E (2016) Attenuated presenilin-1 endoproteolysis enhances store-operated calcium currents in neuronal cells. J Neurochem 136(5):1085–1095

    Article  CAS  PubMed  Google Scholar 

  7. Hiltunen M, Helisalmi S, Mannermaa A, Alafuzoff I, Koivisto AM, Lehtovirta M, Pirskanen M, Sulkava R et al (2000) Identification of a novel 4.6-kb genomic deletion in presenilin-1 gene which results in exclusion of exon 9 in a Finnish early onset Alzheimer’s disease family: an Alu core sequence-stimulated recombination? Eur J Hum Genet 8:259–266

    Article  CAS  PubMed  Google Scholar 

  8. Ratovitski T, Slunt HH, Thinakaran G, Price DL, Sisodia SS, Borchelt DR (1997) Endoproteolytic processing and stabilization of wild-type and mutant presenilin. J Biol Chem 272:24536–24541

    Article  CAS  PubMed  Google Scholar 

  9. Woodruff G, Young JE, Martinez FJ, Buen F, Gore A, Kinaga J, Li Z, Yuan SH et al (2013) The presenilin-1 ΔE9 mutation results in reduced γ-secretase activity, but not total loss of PS1 function, in isogenic human stem cells. Cell Rep 5:974–985

    Article  CAS  PubMed  Google Scholar 

  10. Boyle JP, Hettiarachchi NT, Wilkinson JA, Pearson HA, Scragg JL, Lendon C, Al-Owais MM, Kim CB et al (2012) Cellular consequences of the expression of Alzheimer’s disease-causing presenilin 1 mutations in human neuroblastoma (SH-SY5Y) cells. Brain Res 1443:75–88

    Article  CAS  PubMed  Google Scholar 

  11. Brandman O, Liou J, Park WS, Meyer T (2007) STIM2 is a feedback regulator that stabilizes basal cytosolic and endoplasmic reticulum Ca2+ levels. Cell 131:1327–1339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Emptage NJ, Reid CA, Fine A (2001) Calcium stores in hippocampal synaptic boutons mediate short-term plasticity, store-operated Ca2+ entry, and spontaneous transmitter release. Neuron 29:197–208

    Article  CAS  PubMed  Google Scholar 

  13. Baba A, Yasui T, Fujisawa S, Yamada RX, Yamada MK, Nishiyama N, Matsuki N, Ikegaya Y (2003) Activity-evoked capacitative Ca2+ entry: implications in synaptic plasticity. J Neurosci 23:7737–7741

    Article  CAS  PubMed  Google Scholar 

  14. Wu J, Shih HP, Vigont V, Hrdlicka L, Diggins L, Singh C, Mahoney M, Chesworth R et al (2011) Neuronal store-operated calcium entry pathway as a novel therapeutic target for Huntington’s disease treatment. Chem Biol 18:777–793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Brand AH, Perrimon N (1993) Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118:401–415

    CAS  PubMed  Google Scholar 

  16. Karess RE, Rubin GM (1984) Analysis of P transposable element functions in Drosophila. Cell 38:135–146

    Article  CAS  PubMed  Google Scholar 

  17. Rubin GM, Spradling AC (1982) Genetic transformation of Drosophila with transposable element vectors. Science 218:348–353

    Article  CAS  PubMed  Google Scholar 

  18. Spradling AC, Rubin GM (1982) Transposition of cloned P elements into Drosophila germ line chromosomes. Science 218:341–347

    Article  CAS  PubMed  Google Scholar 

  19. Salvaterra PM, Kitamoto T (2001) Drosophila cholinergic neurons and processes visualized with Gal4/UAS-GFP. Brain Res Gene Expr Patterns 1:73–82

    Article  CAS  PubMed  Google Scholar 

  20. Hall JC (1994) The mating of a fly. Science 264:1702–1714

    Article  CAS  PubMed  Google Scholar 

  21. Siegel RW, Hall JC (1979) Conditioned responses in courtship behavior of normal and mutant Drosophila. Proc Natl Acad Sci U S A 76:3430–3434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kamyshev NG, Iliadi KG, Bragina JV (1999) Drosophila conditioned courtship: two ways of testing memory. Learn Mem 6:1–20

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Ambudkar IS, de Souza LB, Ong HL (2016) TRPC1, Orai1, and STIM1 in SOCE: friends in tight spaces. Cell Calcium pii S0143-4160(16):30218–30214

    Google Scholar 

  24. Storch U, Forst AL, Philipp M, Gudermann T, Mederos y Schnitzler, M. (2012) Transient receptor potential channel 1 (TRPC1) reduces calcium permeability in heteromeric channel complexes. J Biol Chem 287:3530–3540

  25. Strübing C, Krapivinsky G, Krapivinsky L, Clapham DE (2003) Formation of novel TRPC channels by complex subunit interactions in embryonic brain. J Biol Chem 278:39014–39019

  26. DeHaven WI, Smyth JT, Boyles RR, Putney JW Jr (2007) Calcium inhibition and calcium potentiation of Orai1, Orai2, and Orai3 calcium release-activated calcium channels. J Biol Chem 282:17548–17556

    Article  CAS  PubMed  Google Scholar 

  27. Gruszczynska-Biegala J, Pomorski P, Wisniewska MB, Kuznicki J (2011) Differential roles for STIM1 and STIM2 in store-operated calcium entry in rat neurons. PLoS One 6:e19285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cheng KT, Ong HL, Liu X, Ambudkar IS (2013) Contribution and regulation of TRPC channels in store-operated Ca2+ entry. Curr Top Membr 71:149–179

    Article  CAS  PubMed  Google Scholar 

  29. Hoth M, Niemeyer BA (2013) The neglected CRAC proteins: Orai2, Orai3, and STIM2. Curr Top Membr 71:237–271

    Article  CAS  PubMed  Google Scholar 

  30. Xia J, Pan R, Gao X, Meucci O, Hu H (2014) Native store-operated calcium channels are functionally expressed in mouse spinal cord dorsal horn neurons and regulate resting calcium homeostasis. J Physiol 592:3443–3461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Majewski L, Kuznicki J (2015) SOCE in neurons: signaling or just refilling? Biochim Biophys Acta 1853(9):1940–1952

    Article  CAS  PubMed  Google Scholar 

  32. Sun Y, Sukumaran P, Bandyopadhyay BC, Singh BB (2014) Physiological function and characterization of TRPCs in neurons. Cell 3:455–475

    Article  CAS  Google Scholar 

  33. Skibinska-Kijek A, Wisniewska MB, Gruszczynska-Biegala J, Methner A, Kuznicki J (2009) Immunolocalization of STIM1 in the mouse brain. Acta Neurobiol Exp (Wars) 69:413–428

    Google Scholar 

  34. Cheng KT, Liu X, Ong HL, Swaim W, Ambudkar IS (2011) Local Ca2+ entry via Orai1 regulates plasma membrane recruitment of TRPC1 and controls cytosolic Ca2+ signals required for specific cell functions. PLoS Biol 9:e1001025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Moloney A, Sattelle DB, Lomas DA, Crowther DC (2010) Alzheimer’s disease: insights from Drosophila melanogaster models. Trends Biochem Sci 35:228–235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Geula C, Mesulam MM (1989) Cortical cholinergic fibers in aging and Alzheimer’s disease: a morphometric study. Neuroscience 33:469–481

    Article  CAS  PubMed  Google Scholar 

  37. McBride SM, Choi CH, Wang Y, Liebelt D, Braunstein E, Ferreiro D, Sehgal A, Siwicki KK et al (2005) Pharmacological rescue of synaptic plasticity, courtship behavior, and mushroom body defects in a Drosophila model of fragile X syndrome. Neuron 45:753–764

    Article  CAS  PubMed  Google Scholar 

  38. Bolduc FV, Bell K, Cox H, Broadie KS, Tully T (2008) Excess protein synthesis in Drosophila fragile X mutants impairs long-term memory. Nat Neurosci 11:1143–1145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Choi CH, McBride SM, Schoenfeld BP, Liebelt DA, Ferreiro D, Ferrick NJ, Hinchey P, Kollaros M et al (2010) Age-dependent cognitive impairment in a Drosophila fragile X model and its pharmacological rescue. Biogerontology 11:347–362

    Article  PubMed  Google Scholar 

  40. Chakraborty R, Vepuri V, Mhatre SD, Paddock BE, Miller S, Michelson SJ, Delvadia R, Desai A et al (2011) Characterization of a Drosophila Alzheimer’s disease model: pharmacological rescue of cognitive defects. PLoS One 6:e20799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Vartiainen S, Chen S, George J, Tuomela T, Luoto KR, O'Dell KM, Jacobs HT (2014) Phenotypic rescue of a Drosophila model of mitochondrial ANT1 disease. Dis Model Mech 7:635–648

    Article  PubMed  PubMed Central  Google Scholar 

  42. Ejima A, Smith BP, Lucas C, Levine JD, Griffith LC (2005) Sequential learning of pheromonal cues modulates memory consolidation in trainer-specific associative courtship conditioning. Curr Biol 15:194–206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ejima A, Smith BP, Lucas C, van der Goes van Naters W, Miller CJ, Carlson JR, Levine JD, Griffith LC (2007) Generalization of courtship learning in Drosophila is mediated by cis-vaccenyl acetate. Curr Biol 17:599–605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bootman MD, Collins TJ, Mackenzie L, Roderick HL, Berridge MJ, Peppiatt CM (2002) 2-aminoethoxydiphenyl borate (2-APB) is a reliable blocker of store-operated Ca2+ entry but an inconsistent inhibitor of InsP3-induced Ca2+ release. FASEB J 16:1145–1150

    Article  CAS  PubMed  Google Scholar 

  45. Koss DJ, Riedel G, Bence K, Platt B (2013) Store-operated Ca2+ entry in hippocampal neurons: regulation by protein tyrosine phosphatase PTP1B. Cell Calcium 53:125–138

    Article  CAS  PubMed  Google Scholar 

  46. Mollet P, Graf U, Würgler FE (1974) Toxicity and mutagenicity of dimethyl sulfoxide in two strains of Drosophila melanogaster. Arch Genet (Zur) 47:184–190

    CAS  Google Scholar 

  47. Nazir A, Mukhopadhyay I, Saxena DK, Chowdhuri DK (2003) Evaluation of the no observed adverse effect level of solvent dimethyl sulfoxide in Drosophila melanogaster. Toxicol Mech Methods 13:147–152

    Article  CAS  PubMed  Google Scholar 

  48. Berridge MJ (2013) Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia. Prion 7:2–13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kann O, Taubenberger N, Huchzermeyer C, Papageorgiou IE, Benninger F, Heinemann U, Kovács R (2012) Muscarinic receptor activation determines the effects of store-operated Ca(2+)-entry on excitability and energy metabolism in pyramidal neurons. Cell Calcium 51:40–50

    Article  CAS  PubMed  Google Scholar 

  50. Mitchell CB, Gasperini RJ, Small DH, Foa L (2012) STIM1 is necessary for store-operated calcium entry in turning growth cones. J Neurochem 122:1155–1166

    Article  CAS  PubMed  Google Scholar 

  51. Shim S, Zheng JQ, Ming GL (2013) A critical role for STIM1 in filopodial calcium entry and axon guidance. Mol Brain 6:51

    Article  PubMed  PubMed Central  Google Scholar 

  52. Somasundaram A, Shum AK, McBride HJ, Kessler JA, Feske S, Miller RJ, Prakriya M (2014) Store-operated CRAC channels regulate gene expression and proliferation in neural progenitor cells. J Neurosci 34:9107–9123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sun S, Zhang H, Liu J, Popugaeva E, Xu NJ, Feske S, White CL 3rd, Bezprozvanny I (2014) Reduced synaptic STIM2 expression and impaired store-operated calcium entry cause destabilization of mature spines in mutant presenilin mice. Neuron 82:79–93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jaworska A, Dzbek J, Styczynska M, Kuznicki J (2013) Analysis of calcium homeostasis in fresh lymphocytes from patients with sporadic Alzheimer’s disease or mild cognitive impairment. Biochim Biophys Acta 1833:1692–1699

    Article  CAS  PubMed  Google Scholar 

  55. Shalygin A, Skopin A, Kalinina V, Zimina O, Glushankova L, Mozhayeva GN, Kaznacheyeva E (2015) STIM1 and STIM2 proteins differently regulate endogenous store-operated channels in HEK293 cells. J Biol Chem 290:4717–4727

    Article  CAS  PubMed  Google Scholar 

  56. Berna-Erro A, Braun A, Kraft R, Kleinschnitz C, Schuhmann MK, Stegner D, Wultsch T, Eilers J et al (2009) STIM2 regulates capacitive Ca2+ entry in neurons and plays a key role in hypoxic neuronal cell death. Sci Signal 2:ra67

    Article  PubMed  Google Scholar 

  57. Asanov A, Sampieri A, Moreno C, Pacheco J, Salgado A, Sherry R, Vaca L (2015) Combined single channel and single molecule detection identifies subunit composition of STIM1-activated transient receptor potential canonical (TRPC) channels. Cell Calcium 57:1–13

    Article  CAS  PubMed  Google Scholar 

  58. Williams RT, Manji SS, Parker NJ, Hancock MS, Van Stekelenburg L, Eid JP, Senior PV, Kazenwadel JS et al (2001) Identification and characterization of the STIM (stromal interaction molecule) gene family: coding for a novel class of transmembrane proteins. Biochem J 357:673–685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Roos J, DiGregorio PJ, Yeromin AV, Ohlsen K, Lioudyno M, Zhang S, Safrina O, Kozak JA et al (2005) STIM1, an essential and conserved component of store-operated Ca2+ channel function. J Cell Biol 169:435–445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Venkiteswaran G, Hasan G (2009) Intracellular Ca2+ signaling and store-operated Ca2+ entry are required in Drosophila neurons for flight. Proc Natl Acad Sci U S A 106:10326–10331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. McBride SM, Choi CH, Schoenfeld BP, Bell AJ, Liebelt DA, Ferreiro D, Choi RJ, Hinchey P et al (2010) Pharmacological and genetic reversal of age-dependent cognitive deficits attributable to decreased presenilin function. J Neurosci 30:9510–9522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Agrawal N, Venkiteswaran G, Sadaf S, Padmanabhan N, Banerjee S, Hasan G (2010) Inositol 1,4,5-trisphosphate receptor and dSTIM function in Drosophila insulin-producing neurons regulates systemic intracellular calcium homeostasis and flight. J Neurosci 30(4):1301–1313

    Article  CAS  PubMed  Google Scholar 

  63. Hu W, He Z, Yang L, Zhang M, Xing D, Xiao Z (2014) 2-aminoethoxydiphenyl borate (2-APB) reverses beta amyloid-induced LTP deficit through blocking BAX and caspase-3 hyperactivation. Br J Pharmacol 172:2273–2285

    Article  Google Scholar 

Download references

Acknowledgments

We wish to thank Dr. I. Bezprozvanny (Southwestern Medical Center, Dallas, TX) for providing us with human wild-type PS1 and PS1 ∆E9 expression plasmids. We thank Dr. Stefanie Weidtkamp-Peters from Heinrich-Heine-Universität Düsseldorf, Center for Advanced Imaging (CAi), who helped with live-cell imaging and Dr. Yuri Kaulin for his help in preparing the manuscript. This work was supported by the Russian Scientific Foundation, project no. 14-14-00720 (to M.R. and E.K.), the program of “Molecular and Cellular Biology” RAS (to K.S), the Russian Basic Research Foundation, ERAnet RUS (to A.M. and E.K.), the OPTEC LLC and the President of Russia Scholarship (to M.R.).

Author information

Author notes

  1. Maria Ryazantseva and Anna Goncharova contributed equally.

Authors and Affiliations

  1. Institute of Cytology, Russian Academy of Sciences, 4 Tikhoretsky Ave, St. Petersburg, 194064, Russia

    Maria Ryazantseva, Kseniia Skobeleva & Elena Kaznacheyeva

  2. Pavlov Institute of Physiology, Russian Academy of Sciences, 6 Makarova emb, St. Petersburg, 199034, Russia

    Anna Goncharova

  3. Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilova St, Moscow, 119334, Russia

    Maksim Erokhin & Pavel Georgiev

  4. Department of Neurology, University Medicine, Focus Program Translational Neuroscience (FTN), Rhein-Main-Neuro-Zentrum (rmn2), Langenbeckstraße 1, 55131, Mainz, Germany

    Axel Methner

Authors
  1. Maria Ryazantseva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anna Goncharova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kseniia Skobeleva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maksim Erokhin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Axel Methner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pavel Georgiev
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elena Kaznacheyeva
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.R. performed and designed the research, analyzed the data, and wrote the paper; A.G. performed the research and analyzed the data; K.S. performed the research and analyzed the data, M.E. performed the research; A.M. and P.G. designed the research; and E.K. designed the research and wrote the paper.

Corresponding authors

Correspondence to Maria Ryazantseva or Elena Kaznacheyeva.

Ethics declarations

Conflict of Interest

The authors declare that they have no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ryazantseva, M., Goncharova, A., Skobeleva, K. et al. Presenilin-1 Delta E9 Mutant Induces STIM1-Driven Store-Operated Calcium Channel Hyperactivation in Hippocampal Neurons. Mol Neurobiol 55, 4667–4680 (2018). https://doi.org/10.1007/s12035-017-0674-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-017-0674-4

Keywords

  • Alzheimer’s disease
  • STIM1
  • SOC
  • Drosophila
  • Calcium
  • Calcium channel