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Magnesium Acts as a Second Messenger in the Regulation of NMDA Receptor-Mediated CREB Signaling in Neurons

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Abstract

Extracellular magnesium ion ([Mg2+]) is a well-known voltage-dependent blocker of NMDA receptors, which plays a critical role in the regulation of neuronal plasticity, learning, and memory. It is generally believed that NMDA receptor activation involves in Mg2+ being removed into extracellular compartment from the channel pore. On the other hand, Mg2+ is one of the most abundant intracellular cations, and involved in numerous cellular functions. However, we do not know if extracellular magnesium ions can influx into neurons to affect intracellular signaling pathways. In our current study, we found that extracellular [Mg2+] elevation enhanced CREB activation by NMDA receptor signaling in both mixed sex rat cultured neurons and brain slices. Moreover, we found that extracellular [Mg2+] led to CREB activation by NMDA application, albeit in a delayed manner, even in the absence of extracellular calcium, suggesting a potential independent role of magnesium in CREB activation. Consistent with this, we found that NMDA application leads to an NMDAR-dependent increase in intracellular-free [Mg2+] in cultured neurons in the absence of extracellular calcium. Chelating this magnesium influx or inhibiting P38 mitogen-activated protein kinase (p38 MAPK) blocked the delayed pCREB by NMDA. Finally, we found that NMDAR signaling in the absence of extracellular calcium activates p38 MAPK. Our studies thus indicate that magnesium influx, dependent on NMDA receptor opening, can transduce a signaling pathway to activate CREB in neurons.

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References

  1. Romani AM (2007) Magnesium homeostasis in mammalian cells. Front Biosci 12:308–331

    CAS  PubMed  Google Scholar 

  2. Billard JM (2011) Brain free magnesium homeostasis as a target for reducing cognitive aging. In: Vink R, Nechifor M (eds) Magnesium in the central nervous system, Adelaide

  3. Turner RJ, Vink R (2006) Magnesium in the Central Nervous System. In: New perspectives in magnesium research, pp. 338–355

    Google Scholar 

  4. Vink R, Nechifor M (2011) Magnesium in the central nervous system. Univ of Adelaide Press, Adelaide, pp. 338–355

    Google Scholar 

  5. Slutsky I, Abumaria N, Wu LJ, Huang C, Zhang L, Li B, Zhao X, Govindarajan A et al (2010) Enhancement of learning and memory by elevating brain magnesium. Neuron 65:165–177

    CAS  PubMed  Google Scholar 

  6. Mayer ML, Westbrook GL (1987) Permeation and block of N-methyl-D-aspartic acid receptor channels by divalent cations in mouse cultured central neurones. J Physiol 394:501–527

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Mayer ML, Westbrook GL, Guthrie PB (1984) Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature 309:261–263

    CAS  PubMed  Google Scholar 

  8. Nowak L, Bregestovski P, Ascher P, Herbet A, Prochiantz A (1984) Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307:462–465

    CAS  PubMed  Google Scholar 

  9. Brocard JB, Rajdev S, Reynolds IJ (1993) Glutamate-induced increases in intracellular free Mg2+ in cultured cortical neurons. Neuron 11:751–757

    CAS  PubMed  Google Scholar 

  10. Antonov SM, Johnson JW (1999) Permeant ion regulation of N-methyl-D-aspartate receptor channel block by mg(2+). Proc Natl Acad Sci U S A 96:14571–14576

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Qian A, Johnson JW (2006) Permeant ion effects on external Mg2+ block of NR1/2D NMDA receptors. J Neurosci 26:10899–10910

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Qian A, Antonov SM, Johnson JW (2002) Modulation by permeant ions of mg(2+) inhibition of NMDA-activated whole-cell currents in rat cortical neurons. J Physiol 538:65–77

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Stout AK, Li-Smerin Y, Johnson JW, Reynolds IJ (1996) Mechanisms of glutamate-stimulated Mg2+ influx and subsequent Mg2+ efflux in rat forebrain neurones in culture. J Physiol 492(Pt 3):641–657

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Lonze BE, Ginty DD (2002) Function and regulation of CREB family transcription factors in the nervous system. Neuron 35:605–623

    CAS  PubMed  Google Scholar 

  15. West AE, Chen WG, Dalva MB, Dolmetsch RE, Kornhauser JM, Shaywitz AJ, Takasu MA, Tao X et al (2001) Calcium regulation of neuronal gene expression. Proc Natl Acad Sci U S A 98:11024–11031

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Deisseroth K, Mermelstein PG, Xia H, Tsien RW (2003) Signaling from synapse to nucleus: The logic behind the mechanisms. Curr Opin Neurobiol 13:354–365

    CAS  PubMed  Google Scholar 

  17. Hardingham GE, Fukunaga Y, Bading H (2002) Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci 5:405–414

    CAS  PubMed  Google Scholar 

  18. Sala C, Rudolph-Correia S, Sheng M (2000) Developmentally regulated NMDA receptor-dependent dephosphorylation of cAMP response element-binding protein (CREB) in hippocampal neurons. J Neurosci 20:3529–3536

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Siddoway BHH, Xia H (2011) Glutamatergic synapses: molecular organisation. eLS. https://doi.org/10.1002/9780470015902.a0000235.pub2

  20. Guindi C, Cloutier A, Gaudreau S, Zerif E, McDonald PP, Tatsiy O, Asselin C, Dupuis G et al (2018) Role of the p38 MAPK/C/EBPbeta pathway in the regulation of phenotype and IL-10 and IL-12 production by Tolerogenic bone marrow-derived dendritic cells. Cells 7

  21. Park JM, Greten FR, Wong A, Westrick RJ, Arthur JS, Otsu K, Hoffmann A, Montminy M et al (2005) Signaling pathways and genes that inhibit pathogen-induced macrophage apoptosis--CREB and NF-kappaB as key regulators. Immunity 23:319–329

    CAS  PubMed  Google Scholar 

  22. Roskoski R Jr (2015) A historical overview of protein kinases and their targeted small molecule inhibitors. Pharmacol Res 100:1–23

    CAS  PubMed  Google Scholar 

  23. Waas WF, Rainey MA, Szafranska AE, Cox K, Dalby KN (2004) A kinetic approach towards understanding substrate interactions and the catalytic mechanism of the serine/threonine protein kinase ERK2: Identifying a potential regulatory role for divalent magnesium. Biochim Biophys Acta 1697:81–87

    CAS  PubMed  Google Scholar 

  24. Gao J, Hu XD, Yang H, Xia H (2018) Distinct roles of protein phosphatase 1 bound on Neurabin and Spinophilin and its regulation in AMPA receptor trafficking and LTD induction. Mol Neurobiol 55:7179–7186

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Siddoway B, Hou H, Yang H, Petralia R, Xia H (2014a) Synaptic activity bidirectionally regulates a novel sequence-specific S-Q phosphoproteome in neurons. J Neurochem 128:841–851

    CAS  PubMed  Google Scholar 

  26. Siddoway B, Hou H, Yang J, Sun L, Yang H, Wang GY, Xia H (2014b) Potassium channel Kv2.1 is regulated through protein phosphatase-1 in response to increases in synaptic activity. Neurosci Lett 583:142–147

    CAS  PubMed  Google Scholar 

  27. Hou H, Sun L, Siddoway BA, Petralia RS, Yang H, Gu H, Nairn AC, Xia H (2013) Synaptic NMDA receptor stimulation activates PP1 by inhibiting its phosphorylation by Cdk5. J Cell Biol 203:521–535

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Hu XD, Huang Q, Roadcap DW, Shenolikar SS, Xia H (2006) Actin-associated neurabin-protein phosphatase-1 complex regulates hippocampal plasticity. J Neurochem 98:1841–1851

    CAS  PubMed  Google Scholar 

  29. Karpova A, Mikhaylova M, Bera S, Bar J, Reddy PP, Behnisch T, Rankovic V, Spilker C et al (2013) Encoding and transducing the synaptic or extrasynaptic origin of NMDA receptor signals to the nucleus. Cell 152:1119–1133

    CAS  PubMed  Google Scholar 

  30. Hou H, Chavez AE, Wang CC, Yang H, Gu H, Siddoway BA, Hall BJ, Castillo PE et al (2014) The Rac1 inhibitor NSC23766 suppresses CREB signaling by targeting NMDA receptor function. J Neurosci 34:14006–14012

    PubMed  PubMed Central  Google Scholar 

  31. Zhu JJ, Esteban JA, Hayashi Y, Malinow R (2000) Postnatal synaptic potentiation: Delivery of GluR4-containing AMPA receptors by spontaneous activity. Nat Neurosci 3:1098–1106

    CAS  PubMed  Google Scholar 

  32. Romani AM (2011) Cellular magnesium homeostasis. Arch Biochem Biophys 512:1–23

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Bito H, Deisseroth K, Tsien RW (1996) CREB phosphorylation and dephosphorylation: A Ca(2+)- and stimulus duration-dependent switch for hippocampal gene expression. Cell 87:1203–1214

    CAS  PubMed  Google Scholar 

  34. Yang H, Hou H, Pahng A, Gu H, Nairn AC, Tang YP, Colombo PJ, Xia H (2015) Protein Phosphatase-1 Inhibitor-2 is a novel memory suppressor. J Neurosci 35:15082–15087

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Easom RA, Tarpley JL, Filler NR, Bhatt H (1998) Dephosphorylation and deactivation of Ca2+/calmodulin-dependent protein kinase II in betaTC3-cells is mediated by Mg2+− and okadaic-acid-sensitive protein phosphatases. Biochem J 329(Pt 2):283–288

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Kim SJ, Lee SJ, Kim JS, Kang HS (2008) High extracellular [Mg2+]-induced increase in intracellular [Mg2+] and decrease in intracellular [Na+] are associated with activation of p38 MAP kinase and ERK2 in Guinea-pig heart. Exp Physiol 93:1223–1232

    CAS  PubMed  Google Scholar 

  37. Rouse J, Cohen P, Trigon S, Morange M, Alonso-Llamazares A, Zamanillo D, Hunt T, Nebreda AR (1994) A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell 78:1027–1037

    CAS  PubMed  Google Scholar 

  38. Clapham DE (2007) Calcium signaling. Cell 131:1047–1058

    CAS  PubMed  Google Scholar 

  39. Li FY, Chaigne-Delalande B, Kanellopoulou C, Davis JC, Matthews HF, Douek DC, Cohen JI, Uzel G et al (2011) Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature 475:471–476

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Sutherland EW (1972) Studies on the mechanism of hormone action. Science 177:401–408

    CAS  PubMed  Google Scholar 

  41. Takaya J, Higashino H, Kobayashi Y (2000) Can magnesium act as a second messenger? Current data on translocation induced by various biologically active substances. Magnes Res 13:139–146

    CAS  PubMed  Google Scholar 

  42. Yamanaka R, Shindo Y, Hotta K, Suzuki K, Oka K (2018) GABA-induced intracellular mg(2+) mobilization integrates and coordinates cellular information processing for the maturation of neural networks. Curr Biol 28(3984–3991):e3985

    Google Scholar 

  43. Liao W, Jiang M, Li M, Jin C, Xiao S, Fan S, Fang W, Zheng Y et al (2017) Magnesium elevation promotes neuronal differentiation while suppressing glial differentiation of primary cultured adult mouse neural progenitor cells through ERK/CREB activation. Front Neurosci 11:87

    PubMed  PubMed Central  Google Scholar 

  44. Lee HK, Kameyama K, Huganir RL, Bear MF (1998) NMDA induces long-term synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus. Neuron 21:1151–1162

    CAS  PubMed  Google Scholar 

  45. Barco A, Alarcon JM, Kandel ER (2002) Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell 108:689–703

    CAS  PubMed  Google Scholar 

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Funding

This work is supported by NIH (R01 MH109719), NSF (IOS-1457336) to HX, NIH (R01 DE014756) to D. Y. We would like to thank Dr. Jon Johnson (U. Pittsburgh) for helpful discussions regarding this work.

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Authors and Affiliations

  1. Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, 14642, USA

    Hailong Hou, Liwei Wang, Tianyue Fu, David I. Yule & Houhui Xia

  2. Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY, 14642, USA

    Makaia Papasergi

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  1. Hailong Hou
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  2. Liwei Wang
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  3. Tianyue Fu
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  4. Makaia Papasergi
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Correspondence to Houhui Xia.

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Highlights

Calcium is the well-known trigger for CREB phosphorylation and activation in neurons; however, we found that another divalent ion, extracellular magnesium, could also positively regulate CREB phosphorylation and activation, in an NMDA receptor-dependent manner. Extracellular magnesium can flux into neurons to potentiate p38 MAPK pathway leading to increased CREB phosphorylation. This novel magnesium-mediated CREB signaling pathway has a slower onset and can be activated by both mild and strong NMDA receptor activation, indicating a potential relevance to both physiological and pathological role in our brain.

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Hou, H., Wang, L., Fu, T. et al. Magnesium Acts as a Second Messenger in the Regulation of NMDA Receptor-Mediated CREB Signaling in Neurons. Mol Neurobiol 57, 2539–2550 (2020). https://doi.org/10.1007/s12035-020-01871-z

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  • DOI: https://doi.org/10.1007/s12035-020-01871-z

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