Advertisement

Molecular Neurobiology

, Volume 56, Issue 12, pp 8345–8363 | Cite as

NMDA Receptors Regulate Neuregulin 2 Binding to ER-PM Junctions and Ectodomain Release

  • Detlef Vullhorst
  • Andres BuonannoEmail author
Article
  • 230 Downloads

Abstract

Unprocessed pro-neuregulin 2 (pro-NRG2) accumulates on neuronal cell bodies at junctions between the endoplasmic reticulum and plasma membrane (ER-PM junctions). NMDA receptors (NMDARs) trigger NRG2 ectodomain shedding from these sites followed by activation of ErbB4 receptor tyrosine kinases, and ErbB4 signaling cell-autonomously downregulates intrinsic excitability of GABAergic interneurons by reducing voltage-gated sodium channel currents. NMDARs also promote dispersal of Kv2.1 clusters from ER-PM junctions and cause a hyperpolarizing shift in its voltage-dependent channel activation, suggesting that NRG2/ErbB4 and Kv2.1 work together to regulate intrinsic interneuron excitability in an activity-dependent manner. Here we explored the cellular processes underlying NMDAR-dependent NRG2 shedding in cultured rat hippocampal neurons. We report that NMDARs control shedding by two separate but converging mechanisms. First, NMDA treatment disrupts binding of pro-NRG2 to ER-PM junctions by post-translationally modifying conserved Ser/Thr residues in its intracellular domain. Second, using a mutant NRG2 protein that cannot be modified at these residues and that fails to accumulate at ER-PM junctions, we demonstrate that NMDARs also directly promote NRG2 shedding by ADAM-type metalloproteinases. Using pharmacological and shRNA-mediated knockdown, and metalloproteinase overexpression, we unexpectedly find that ADAM10, but not ADAM17/TACE, is the major NRG2 sheddase acting downstream of NMDAR activation. Together, these findings reveal how NMDARs exert tight control over the NRG2/ErbB4 signaling pathway, and suggest that NRG2 and Kv2.1 are co-regulated components of a shared pathway that responds to elevated extracellular glutamate levels.

Keywords

Neuregulin Kv2.1 ADAM10 ER-PM junction Sheddase Activity-dependent 

Notes

Acknowledgments

We are grateful to Kate McDaniel for help with cloning ADAM10 and ADAM17 constructs, and Drs. Vincent Schram and Carolyn Smith from the Porter Neuroscience Center imaging core for expert assistance with confocal microscopy.

Funding Information

This work was supported by the intramural research program of the Eunice Kennedy Shriver Institute of Child Health and Human Development (NICHD; ZIA-HD000711).

Compliance with Ethical Standards

Animals were treated in accordance with NIH Animal Welfare guidelines. All procedures were approved by the NICHD Animal Care and User Committee.

Supplementary material

12035_2019_1659_MOESM1_ESM.pdf (2.8 mb)
ESM 1 (PDF 2850 kb)
12035_2019_1659_MOESM2_ESM.avi (2.8 mb)
Online Resource 1 (AVI 2821 kb)
12035_2019_1659_MOESM3_ESM.avi (1.6 mb)
Online Resource 2 (AVI 1649 kb)

References

  1. 1.
    Gerecke KM, Wyss JM, Karavanova I, Buonanno A, Carroll SL (2001) ErbB transmembrane tyrosine kinase receptors are differentially expressed throughout the adult rat central nervous system. J Comp Neurol 433(1):86–100CrossRefGoogle Scholar
  2. 2.
    Buonanno A, Fischbach GD (2001) Neuregulin and ErbB receptor signaling pathways in the nervous system. Curr Opin Neurobiol 11(3):287–296CrossRefGoogle Scholar
  3. 3.
    Birchmeier C, Nave KA (2008) Neuregulin-1, a key axonal signal that drives Schwann cell growth and differentiation. Glia 56(14):1491–1497.  https://doi.org/10.1002/glia.20753 CrossRefPubMedGoogle Scholar
  4. 4.
    Buonanno A (2010) The neuregulin signaling pathway and schizophrenia: from genes to synapses and neural circuits. Brain Res Bull 83(3–4):122–131.  https://doi.org/10.1016/j.brainresbull.2010.07.012 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Mei L, Nave KA (2014) Neuregulin-ERBB signaling in the nervous system and neuropsychiatric diseases. Neuron 83(1):27–49.  https://doi.org/10.1016/j.neuron.2014.06.007 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Mostaid MS, Lloyd D, Liberg B, Sundram S, Pereira A, Pantelis C, Karl T, Weickert CS et al (2016) Neuregulin-1 and schizophrenia in the genome-wide association study era. Neurosci Biobehav Rev 68:387–409.  https://doi.org/10.1016/j.neubiorev.2016.06.001
  7. 7.
    Chung DW, Volk DW, Arion D, Zhang Y, Sampson AR, Lewis DA (2016) Dysregulated ErbB4 splicing in schizophrenia: selective effects on parvalbumin expression. Am J Psychiatry 173(1):60–68.  https://doi.org/10.1176/appi.ajp.2015.15020150 CrossRefPubMedGoogle Scholar
  8. 8.
    Woo RS, Li XM, Tao Y, Carpenter-Hyland E, Huang YZ, Weber J, Neiswender H, Dong XP et al (2007) Neuregulin-1 enhances depolarization-induced GABA release. Neuron 54(4):599–610.  https://doi.org/10.1016/j.neuron.2007.04.009
  9. 9.
    Chen YJ, Johnson MA, Lieberman MD, Goodchild RE, Schobel S, Lewandowski N, Rosoklija G, Liu RC et al (2008) Type III neuregulin-1 is required for normal sensorimotor gating, memory-related behaviors, and corticostriatal circuit components. J Neurosci 28(27):6872–6883.  https://doi.org/10.1523/JNEUROSCI.1815-08.2008
  10. 10.
    Kwon OB, Paredes D, Gonzalez CM, Neddens J, Hernandez L, Vullhorst D, Buonanno A (2008) Neuregulin-1 regulates LTP at CA1 hippocampal synapses through activation of dopamine D4 receptors. Proc Natl Acad Sci U S A 105(40):15587–15592.  https://doi.org/10.1073/pnas.0805722105 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Fisahn A, Neddens J, Yan L, Buonanno A (2009) Neuregulin-1 modulates hippocampal gamma oscillations: implications for schizophrenia. Cereb Cortex 19(3):612–618.  https://doi.org/10.1093/cercor/bhn107 CrossRefPubMedGoogle Scholar
  12. 12.
    Andersson RH, Johnston A, Herman PA, Winzer-Serhan UH, Karavanova I, Vullhorst D, Fisahn A, Buonanno A (2012) Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors. Proc Natl Acad Sci U S A 109(32):13118–13123.  https://doi.org/10.1073/pnas.1201011109 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Del Pino I, Garcia-Frigola C, Dehorter N, Brotons-Mas JR, Alvarez-Salvado E, Martinez de Lagran M, Ciceri G, Gabaldon MV et al (2013) Erbb4 deletion from fast-spiking interneurons causes schizophrenia-like phenotypes. Neuron 79(6):1152–1168.  https://doi.org/10.1016/j.neuron.2013.07.010
  14. 14.
    Yin DM, Chen YJ, Lu YS, Bean JC, Sathyamurthy A, Shen C, Liu X, Lin TW et al (2013) Reversal of behavioral deficits and synaptic dysfunction in mice overexpressing neuregulin 1. Neuron 78(4):644–657.  https://doi.org/10.1016/j.neuron.2013.03.028
  15. 15.
    Loos M, Mueller T, Gouwenberg Y, Wijnands R, van der Loo RJ, Neuro BMPC, Birchmeier C, Smit AB et al (2014) Neuregulin-3 in the mouse medial prefrontal cortex regulates impulsive action. Biol Psychiatry 76(8):648–655.  https://doi.org/10.1016/j.biopsych.2014.02.011
  16. 16.
    Gu Y, Tran T, Murase S, Borrell A, Kirkwood A, Quinlan EM (2016) Neuregulin-dependent regulation of fast-spiking interneuron excitability controls the timing of the critical period. J Neurosci 36(40):10285–10295.  https://doi.org/10.1523/JNEUROSCI.4242-15.2016 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Sun Y, Ikrar T, Davis MF, Gong N, Zheng X, Luo ZD, Lai C, Mei L et al (2016) Neuregulin-1/ErbB4 signaling regulates visual cortical plasticity. Neuron 92(1):160–173.  https://doi.org/10.1016/j.neuron.2016.08.033
  18. 18.
    Zhong C, Akmentin W, Du C, Role LW, Talmage DA (2017) Axonal type III Nrg1 controls glutamate synapse formation and GluA2 trafficking in hippocampal-accumbens connections. eNeuro 4(1).  https://doi.org/10.1523/ENEURO.0232-16.2017
  19. 19.
    Muller T, Braud S, Juttner R, Voigt BC, Paulick K, Sheean ME, Klisch C, Gueneykaya D et al (2018) Neuregulin 3 promotes excitatory synapse formation on hippocampal interneurons. EMBO J 37(17).  https://doi.org/10.15252/embj.201798858
  20. 20.
    Tan Z, Robinson HL, Yin DM, Liu Y, Liu F, Wang H, Lin TW, Xing G et al (2018) Dynamic ErbB4 activity in hippocampal-prefrontal synchrony and top-down attention in rodents. Neuron 98(2):380–393.  https://doi.org/10.1016/j.neuron.2018.03.018
  21. 21.
    Yan L, Shamir A, Skirzewski M, Leiva-Salcedo E, Kwon OB, Karavanova I, Paredes D, Malkesman O et al (2018) Neuregulin-2 ablation results in dopamine dysregulation and severe behavioral phenotypes relevant to psychiatric disorders. Mol Psychiatry 23(5):1233–1243.  https://doi.org/10.1038/mp.2017.22
  22. 22.
    Yang JM, Shen CJ, Chen XJ, Kong Y, Liu YS, Li XW, Chen Z, Gao TM et al (2018) erbb4 deficits in chandelier cells of the medial prefrontal cortex confer cognitive dysfunctions: implications for schizophrenia. Cereb Cortex.  https://doi.org/10.1093/cercor/bhy316
  23. 23.
    Deakin IH, Godlewska BR, Walker MA, Huang GJ, Schwab MH, Nave KA, Law AJ, Harrison PJ (2018) Altered hippocampal gene expression and structure in transgenic mice overexpressing neuregulin 1 (Nrg1) type I. Transl Psychiatry 8(1):229.  https://doi.org/10.1038/s41398-018-0288-2 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Loeb JA, Susanto ET, Fischbach GD (1998) The neuregulin precursor proARIA is processed to ARIA after expression on the cell surface by a protein kinase C-enhanced mechanism. Mol Cell Neurosci 11(1–2):77–91.  https://doi.org/10.1006/mcne.1998.0676 CrossRefPubMedGoogle Scholar
  25. 25.
    Wang JY, Miller SJ, Falls DL (2001) The N-terminal region of neuregulin isoforms determines the accumulation of cell surface and released neuregulin ectodomain. J Biol Chem 276(4):2841–2851.  https://doi.org/10.1074/jbc.M005700200
  26. 26.
    Falls DL (2003) Neuregulins: functions, forms, and signaling strategies. Exp Cell Res 284(1):14–30CrossRefGoogle Scholar
  27. 27.
    Longart M, Liu Y, Karavanova I, Buonanno A (2004) Neuregulin-2 is developmentally regulated and targeted to dendrites of central neurons. J Comp Neurol 472(2):156–172.  https://doi.org/10.1002/cne.20016 CrossRefPubMedGoogle Scholar
  28. 28.
    Carraway KL 3rd, Weber JL, Unger MJ, Ledesma J, Yu N, Gassmann M, Lai C (1997) Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases. Nature 387(6632):512–516.  https://doi.org/10.1038/387512a0 CrossRefPubMedGoogle Scholar
  29. 29.
    Vullhorst D, Mitchell RM, Keating C, Roychowdhury S, Karavanova I, Tao-Cheng JH, Buonanno A (2015) A negative feedback loop controls NMDA receptor function in cortical interneurons via neuregulin 2/ErbB4 signalling. Nat Commun 6:7222.  https://doi.org/10.1038/ncomms8222 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Kotzadimitriou D, Nissen W, Paizs M, Newton K, Harrison PJ, Paulsen O, Lamsa K (2018) Neuregulin 1 type I overexpression is associated with reduced NMDA receptor-mediated synaptic signaling in hippocampal interneurons expressing PV or CCK. eNeuro 5(2).  https://doi.org/10.1523/ENEURO.0418-17.2018
  31. 31.
    Janssen MJ, Leiva-Salcedo E, Buonanno A (2012) Neuregulin directly decreases voltage-gated sodium current in hippocampal ErbB4-expressing interneurons. J Neurosci 32(40):13889–13895.  https://doi.org/10.1523/JNEUROSCI.1420-12.2012 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Saheki Y, De Camilli P (2017) Endoplasmic reticulum-plasma membrane contact sites. Annu Rev Biochem 86:659–684.  https://doi.org/10.1146/annurev-biochem-061516-044932 CrossRefPubMedGoogle Scholar
  33. 33.
    Takeshima H, Hoshijima M, Song LS (2015) Ca microdomains organized by junctophilins. Cell Calcium 58:349–356.  https://doi.org/10.1016/j.ceca.2015.01.007 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Carrasco S, Meyer T (2011) STIM proteins and the endoplasmic reticulum-plasma membrane junctions. Annu Rev Biochem 80:973–1000.  https://doi.org/10.1146/annurev-biochem-061609-165311 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Rosenbluth J (1962) Subsurface cisterns and their relationship to the neuronal plasma membrane. J Cell Biol 13:405–421CrossRefGoogle Scholar
  36. 36.
    Vullhorst D, Ahmad T, Karavanova I, Keating C, Buonanno A (2017) Structural similarities between neuregulin 1-3 isoforms determine their subcellular distribution and signaling mode in central neurons. J Neurosci 37(21):5232–5249.  https://doi.org/10.1523/JNEUROSCI.2630-16.2017 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Gallart-Palau X, Tarabal O, Casanovas A, Sabado J, Correa FJ, Hereu M, Piedrafita L, Caldero J et al (2014) Neuregulin-1 is concentrated in the postsynaptic subsurface cistern of C-bouton inputs to alpha-motoneurons and altered during motoneuron diseases. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 28(8):3618–3632.  https://doi.org/10.1096/fj.13-248583
  38. 38.
    Salvany S, Casanovas A, Tarabal O, Piedrafita L, Hernandez S, Santafe M, Soto-Bernardini MC, Caldero J, Schwab MH, Esquerda JE (2019) Localization and dynamic changes of neuregulin-1 at C-type synaptic boutons in association with motor neuron injury and repair. FASEB journal : official publication of the Federation of American Societies for Experimental Biology:fj201802329R. doi: https://doi.org/10.1096/fj.201802329R
  39. 39.
    Wolpowitz D, Mason TB, Dietrich P, Mendelsohn M, Talmage DA, Role LW (2000) Cysteine-rich domain isoforms of the neuregulin-1 gene are required for maintenance of peripheral synapses. Neuron 25(1):79–91CrossRefGoogle Scholar
  40. 40.
    Bao J, Wolpowitz D, Role LW, Talmage DA (2003) Back signaling by the Nrg-1 intracellular domain. J Cell Biol 161(6):1133–1141.  https://doi.org/10.1083/jcb.200212085jcb.200212085 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Hancock ML, Canetta SE, Role LW, Talmage DA (2008) Presynaptic type III neuregulin1-ErbB signaling targets {alpha}7 nicotinic acetylcholine receptors to axons. J Cell Biol 181(3):511–521.  https://doi.org/10.1083/jcb.200710037 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Trimmer JS (1991) Immunological identification and characterization of a delayed rectifier K+ channel polypeptide in rat brain. Proc Natl Acad Sci U S A 88(23):10764–10768CrossRefGoogle Scholar
  43. 43.
    Murakoshi H, Trimmer JS (1999) Identification of the Kv2.1 K+ channel as a major component of the delayed rectifier K+ current in rat hippocampal neurons. J Neurosci 19(5):1728–1735CrossRefGoogle Scholar
  44. 44.
    Malin SA, Nerbonne JM (2002) Delayed rectifier K+ currents, IK, are encoded by Kv2 alpha-subunits and regulate tonic firing in mammalian sympathetic neurons. J Neurosci 22(23):10094–10105CrossRefGoogle Scholar
  45. 45.
    Misonou H, Mohapatra DP, Park EW, Leung V, Zhen D, Misonou K, Anderson AE, Trimmer JS (2004) Regulation of ion channel localization and phosphorylation by neuronal activity. Nat Neurosci 7(7):711–718.  https://doi.org/10.1038/nn1260nn1260 CrossRefPubMedGoogle Scholar
  46. 46.
    Benson DL, Watkins FH, Steward O, Banker G (1994) Characterization of GABAergic neurons in hippocampal cell cultures. J Neurocytol 23(5):279–295CrossRefGoogle Scholar
  47. 47.
    Loeb JA, Fischbach GD (1995) ARIA can be released from extracellular matrix through cleavage of a heparin-binding domain. J Cell Biol 130(1):127–135CrossRefGoogle Scholar
  48. 48.
    Tamura H, Kawata M, Hamaguchi S, Ishikawa Y, Shiosaka S (2012) Processing of neuregulin-1 by neuropsin regulates GABAergic neuron to control neural plasticity of the mouse hippocampus. J Neurosci 32(37):12657–12672.  https://doi.org/10.1523/JNEUROSCI.2542-12.2012 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Park KS, Mohapatra DP, Misonou H, Trimmer JS (2006) Graded regulation of the Kv2.1 potassium channel by variable phosphorylation. Science 313(5789):976–979.  https://doi.org/10.1126/science.1124254 CrossRefPubMedGoogle Scholar
  50. 50.
    Montero JC, Yuste L, Diaz-Rodriguez E, Esparis-Ogando A, Pandiella A (2000) Differential shedding of transmembrane neuregulin isoforms by the tumor necrosis factor-alpha-converting enzyme. Mol Cell Neurosci 16(5):631–648.  https://doi.org/10.1006/mcne.2000.0896 CrossRefPubMedGoogle Scholar
  51. 51.
    La Marca R, Cerri F, Horiuchi K, Bachi A, Feltri ML, Wrabetz L, Blobel CP, Quattrini A et al (2011) TACE (ADAM17) inhibits Schwann cell myelination. Nat Neurosci 14(7):857–865.  https://doi.org/10.1038/nn.2849
  52. 52.
    Fleck D, van Bebber F, Colombo A, Galante C, Schwenk BM, Rabe L, Hampel H, Novak B et al (2013) Dual cleavage of neuregulin 1 type III by BACE1 and ADAM17 liberates its EGF-like domain and allows paracrine signaling. J Neurosci 33(18):7856–7869.  https://doi.org/10.1523/JNEUROSCI.3372-12.2013
  53. 53.
    Iwakura Y, Wang R, Inamura N, Araki K, Higashiyama S, Takei N, Nawa H (2017) Glutamate-dependent ectodomain shedding of neuregulin-1 type II precursors in rat forebrain neurons. PLoS One 12(3):e0174780.  https://doi.org/10.1371/journal.pone.0174780 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Lan JY, Skeberdis VA, Jover T, Grooms SY, Lin Y, Araneda RC, Zheng X, Bennett MV et al (2001) Protein kinase C modulates NMDA receptor trafficking and gating. Nat Neurosci 4(4):382–390.  https://doi.org/10.1038/86028
  55. 55.
    Kim J, Lilliehook C, Dudak A, Prox J, Saftig P, Federoff HJ, Lim ST (2010) Activity-dependent alpha-cleavage of nectin-1 is mediated by a disintegrin and metalloprotease 10 (ADAM10). J Biol Chem 285(30):22919–22926.  https://doi.org/10.1074/jbc.M110.126649
  56. 56.
    Suzuki K, Hayashi Y, Nakahara S, Kumazaki H, Prox J, Horiuchi K, Zeng M, Tanimura S et al (2012) Activity-dependent proteolytic cleavage of neuroligin-1. Neuron 76(2):410–422.  https://doi.org/10.1016/j.neuron.2012.10.003
  57. 57.
    Ludwig A, Hundhausen C, Lambert MH, Broadway N, Andrews RC, Bickett DM, Leesnitzer MA, Becherer JD (2005) Metalloproteinase inhibitors for the disintegrin-like metalloproteinases ADAM10 and ADAM17 that differentially block constitutive and phorbol ester-inducible shedding of cell surface molecules. Comb Chem High Throughput Screen 8(2):161–171CrossRefGoogle Scholar
  58. 58.
    Parra LM, Hartmann M, Schubach S, Li Y, Herrlich P, Herrlich A (2015) Distinct intracellular domain substrate modifications selectively regulate ectodomain cleavage of NRG1 or CD44. Mol Cell Biol 35(19):3381–3395.  https://doi.org/10.1128/MCB.00500-15 CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Horiuchi K, Zhou HM, Kelly K, Manova K, Blobel CP (2005) Evaluation of the contributions of ADAMs 9, 12, 15, 17, and 19 to heart development and ectodomain shedding of neuregulins beta1 and beta2. Dev Biol 283(2):459–471.  https://doi.org/10.1016/j.ydbio.2005.05.004 CrossRefPubMedGoogle Scholar
  60. 60.
    Du J, Haak LL, Phillips-Tansey E, Russell JT, McBain CJ (2000) Frequency-dependent regulation of rat hippocampal somato-dendritic excitability by the K+ channel subunit Kv2.1. J Physiol 522(Pt 1):19–31CrossRefGoogle Scholar
  61. 61.
    Misonou H, Mohapatra DP, Menegola M, Trimmer JS (2005) Calcium- and metabolic state-dependent modulation of the voltage-dependent Kv2.1 channel regulates neuronal excitability in response to ischemia. J Neurosci 25(48):11184–11193.  https://doi.org/10.1523/JNEUROSCI.3370-05.2005 CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Shah NH, Aizenman E (2014) Voltage-gated potassium channels at the crossroads of neuronal function, ischemic tolerance, and neurodegeneration. Transl Stroke Res 5(1):38–58.  https://doi.org/10.1007/s12975-013-0297-7 CrossRefPubMedGoogle Scholar
  63. 63.
    Casanovas A, Salvany S, Lahoz V, Tarabal O, Piedrafita L, Sabater R, Hernandez S, Caldero J et al (2017) Neuregulin 1-ErbB module in C-bouton synapses on somatic motor neurons: molecular compartmentation and response to peripheral nerve injury. Sci Rep 7:40155.  https://doi.org/10.1038/srep40155
  64. 64.
    Murakoshi H, Shi G, Scannevin RH, Trimmer JS (1997) Phosphorylation of the Kv2.1 K+ channel alters voltage-dependent activation. Mol Pharmacol 52(5):821–828CrossRefGoogle Scholar
  65. 65.
    Misonou H, Trimmer JS (2004) Determinants of voltage-gated potassium channel surface expression and localization in mammalian neurons. Crit Rev Biochem Mol Biol 39(3):125–145.  https://doi.org/10.1080/10409230490475417 CrossRefPubMedGoogle Scholar
  66. 66.
    Johnson B, Leek AN, Sole L, Maverick EE, Levine TP, Tamkun MM (2018) Kv2 potassium channels form endoplasmic reticulum/plasma membrane junctions via interaction with VAPA and VAPB. Proc Natl Acad Sci U S A 115(31):E7331–E7340.  https://doi.org/10.1073/pnas.1805757115 CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Kirmiz M, Vierra NC, Palacio S, Trimmer JS (2018) Identification of VAPA and VAPB as Kv2 channel-interacting proteins defining endoplasmic reticulum-plasma membrane junctions in mammalian brain neurons. J Neurosci 38(35):7562–7584.  https://doi.org/10.1523/JNEUROSCI.0893-18.2018 CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Tao-Cheng JH (2018) Activity-dependent decrease in contact areas between subsurface cisterns and plasma membrane of hippocampal neurons. Mol Brain 11(1):23.  https://doi.org/10.1186/s13041-018-0366-7 CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Saftig P, Lichtenthaler SF (2015) The alpha secretase ADAM10: a metalloprotease with multiple functions in the brain. Prog Neurobiol 135:1–20.  https://doi.org/10.1016/j.pneurobio.2015.10.003 CrossRefPubMedGoogle Scholar
  70. 70.
    Willem M (2016) Proteolytic processing of neuregulin-1. Brain Res Bull 126 (Pt 2:178–182.  https://doi.org/10.1016/j.brainresbull.2016.07.003 CrossRefPubMedGoogle Scholar
  71. 71.
    Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, DeStrooper B, Saftig P et al (2006) Control of peripheral nerve myelination by the beta-secretase BACE1. Science 314(5799):664–666.  https://doi.org/10.1126/science.1132341
  72. 72.
    Sanderson MP, Abbott CA, Tada H, Seno M, Dempsey PJ, Dunbar AJ (2006) Hydrogen peroxide and endothelin-1 are novel activators of betacellulin ectodomain shedding. J Cell Biochem 99(2):609–623.  https://doi.org/10.1002/jcb.20968 CrossRefPubMedGoogle Scholar
  73. 73.
    Horiuchi K, Le Gall S, Schulte M, Yamaguchi T, Reiss K, Murphy G, Toyama Y, Hartmann D et al (2007) Substrate selectivity of epidermal growth factor-receptor ligand sheddases and their regulation by phorbol esters and calcium influx. Mol Biol Cell 18(1):176–188.  https://doi.org/10.1091/mbc.E06-01-0014
  74. 74.
    Le Gall SM, Bobe P, Reiss K, Horiuchi K, Niu XD, Lundell D, Gibb DR, Conrad D et al (2009) ADAMs 10 and 17 represent differentially regulated components of a general shedding machinery for membrane proteins such as transforming growth factor alpha, L-selectin, and tumor necrosis factor alpha. Mol Biol Cell 20(6):1785–1794.  https://doi.org/10.1091/mbc.E08-11-1135
  75. 75.
    Marcello E, Gardoni F, Di Luca M, Perez-Otano I (2010) An arginine stretch limits ADAM10 exit from the endoplasmic reticulum. J Biol Chem 285(14):10376–10384.  https://doi.org/10.1074/jbc.M109.055947
  76. 76.
    Matthews AL, Noy PJ, Reyat JS, Tomlinson MG (2017) Regulation of a disintegrin and metalloproteinase (ADAM) family sheddases ADAM10 and ADAM17: the emerging role of tetraspanins and rhomboids. Platelets 28(4):333–341.  https://doi.org/10.1080/09537104.2016.1184751 CrossRefPubMedGoogle Scholar
  77. 77.
    Marcello E, Gardoni F, Mauceri D, Romorini S, Jeromin A, Epis R, Borroni B, Cattabeni F et al (2007) Synapse-associated protein-97 mediates alpha-secretase ADAM10 trafficking and promotes its activity. J Neurosci 27(7):1682–1691.  https://doi.org/10.1523/JNEUROSCI.3439-06.2007
  78. 78.
    Shyu WC, Lin SZ, Chiang MF, Yang HI, Thajeb P, Li H (2004) Neuregulin-1 reduces ischemia-induced brain damage in rats. Neurobiol Aging 25(7):935–944.  https://doi.org/10.1016/j.neurobiolaging.2003.10.012 CrossRefPubMedGoogle Scholar
  79. 79.
    Guo WP, Wang J, Li RX, Peng YW (2006) Neuroprotective effects of neuregulin-1 in rat models of focal cerebral ischemia. Brain Res 1087(1):180–185.  https://doi.org/10.1016/j.brainres.2006.03.007 CrossRefPubMedGoogle Scholar
  80. 80.
    Guan YF, Wu CY, Fang YY, Zeng YN, Luo ZY, Li SJ, Li XW, Zhu XH et al (2015) Neuregulin 1 protects against ischemic brain injury via ErbB4 receptors by increasing GABAergic transmission. Neuroscience 307:151–159.  https://doi.org/10.1016/j.neuroscience.2015.08.047
  81. 81.
    Zhang R, Liu C, Ji Y, Teng L, Guo Y (2018) Neuregulin-1beta plays a neuroprotective role by inhibiting the Cdk5 signaling pathway after cerebral ischemia-reperfusion injury in rats. J Mol Neurosci 66(2):261–272.  https://doi.org/10.1007/s12031-018-1166-3 CrossRefPubMedGoogle Scholar
  82. 82.
    Vullhorst D, Neddens J, Karavanova I, Tricoire L, Petralia RS, McBain CJ, Buonanno A (2009) Selective expression of ErbB4 in interneurons, but not pyramidal cells, of the rodent hippocampus. J Neurosci 29(39):12255–12264.  https://doi.org/10.1523/JNEUROSCI.2454-09.2009 CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Schlander M, Hoyer S, Frotscher M (1988) Glutamate decarboxylase-immunoreactive neurons in the aging rat hippocampus are more resistant to ischemia than CA1 pyramidal cells. Neurosci Lett 91(3):241–246CrossRefGoogle Scholar
  84. 84.
    Frahm C, Haupt C, Witte OW (2004) GABA neurons survive focal ischemic injury. Neuroscience 127(2):341–346.  https://doi.org/10.1016/j.neuroscience.2004.05.027 CrossRefPubMedGoogle Scholar
  85. 85.
    Li KX, Lu YM, Xu ZH, Zhang J, Zhu JM, Zhang JM, Cao SX, Chen XJ et al (2011) Neuregulin 1 regulates excitability of fast-spiking neurons through Kv1.1 and acts in epilepsy. Nat Neurosci 15(2):267–273.  https://doi.org/10.1038/nn.3006
  86. 86.
    Yang JM, Zhang J, Chen XJ, Geng HY, Ye M, Spitzer NC, Luo JH, Duan SM et al (2013) Development of GABA circuitry of fast-spiking basket interneurons in the medial prefrontal cortex of erbb4-mutant mice. J Neurosci 33(50):19724–19733.  https://doi.org/10.1523/JNEUROSCI.1584-13.2013
  87. 87.
    Shamir A, Kwon OB, Karavanova I, Vullhorst D, Leiva-Salcedo E, Janssen MJ, Buonanno A (2012) The importance of the NRG-1/ErbB4 pathway for synaptic plasticity and behaviors associated with psychiatric disorders. J Neurosci 32(9):2988–2997.  https://doi.org/10.1523/JNEUROSCI.1899-11.2012 CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Speca DJ, Ogata G, Mandikian D, Bishop HI, Wiler SW, Eum K, Wenzel HJ, Doisy ET et al (2014) Deletion of the Kv2.1 delayed rectifier potassium channel leads to neuronal and behavioral hyperexcitability. Genes Brain Behav 13(4):394–408.  https://doi.org/10.1111/gbb.12120

Copyright information

© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2019

Authors and Affiliations

  1. 1.Section on Molecular NeurobiologyEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesdaUSA

Personalised recommendations