Ginsenoside Rg1 activated CaMKIIα mediated extracellular signal-regulated kinase/mitogen activated protein kinase signaling pathway

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We carried out this study to investigate the effect of ginsenoside Rg1 on the extracellular signal-regulated kinase/mitogen activated protein kinase (ERK/MAPK) pathway for understanding its effect on synaptic platicity.


Western blotting and immunostaining were used to examine the phosphorylation of ERK1/2, CaMKIIα and cAMP response element binding protein (CREB) in PC12 cells and synaptosomes. The confocal microscopy and fluorescent indicator Fluo-3 was applied to observe the intracellular calcium ion flux.


The phosphorylation of ERK1/2 in PC12 cells and synaptosomes incubated with Rg1 was increased and reached maximum at 4 min. Rg1 also promoted the transient enhancement of upstream calcium ion and activated CaMKIIα, which reached maximum at 2 min. CREB, the downstream protein, was phosphorylated within 8 min in PC12 cells after being incubated with Rg1. Moreover, KN93 partially inhibited the activation of ERK1/2, and PD98059 also partially blocked the phosphorylation of CREB.


Rg1 activated ERK/MAPK pathway by CaMKIIα, and the activation of CREB was not only dependent on ERK induced by Rg1, which may provide an explanation for the effect of Rg1 on long-term potentiation.


  1. 1

    Seger R, Krebs EG . The MAPK signaling cascade. FASEB J 1995; 9: 726–35.

  2. 2

    Obata K, Noguchi K . MAPK activation in nociceptive neurons and pain hypersensitivity. Life Sci 2004; 74: 2643–53.

  3. 3

    Sweatt JD . The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J Neu-rochem 2001; 76: 1–10.

  4. 4

    English JD, Sweatt JD . A requirement for the mitogen-activated protein kinase cascade in hippocampal long term potentiation. J Biol Chem 1997; 272: 19 103–6.

  5. 5

    Schafe GE, Atkins CM, Swank MW, Bauer EP, Sweatt JD, LeDoux JE . Activation of ERK/MAP kinase in the amygdala is required for memory consolidation of pavlovian fear conditioning. J Neurosci 2000; 20: 8177–87.

  6. 6

    Sweatt JD . Mitogen-activated protein kinases in synaptic plasticity and memory. Curr Opin Neurobiol 2004; 14: 311–17.

  7. 7

    English JD, Sweatt JD . Activation of p42 mitogen-activated protein kinase in hippocampal long term potentiation. J Biol Chem 1996; 271: 24 329–32.

  8. 8

    Attele AS, Wu JA, Yuan CS . Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999; 58: 1685–93.

  9. 9

    Radada K, Gilleb G, Moldzioa R, Saitoc H, Rausch W . Ginsenosides Rb1 and Rg1 effects on mesencephalic dopaminergic cells stressed with glutamate. Brain Res 2004; 1021: 41–53.

  10. 10

    Leung KW, Yung KK, Mak NK, Chan YS, Fan TP, Wong RN . Neuroprotective effects of ginsenoside-Rg1 in primary nigral neurons against rotenone toxicity. Neuropharmacology 2007; 52: 827–35.

  11. 11

    Chen XC, Chen LM, Zhu YG, Fang F, Zhou YC, Zhao CH . Involvement of CDK4, pRB, and E2F1 in ginsenoside Rg1 protecting rat cortical neurons from beta-amyloid-induced apoptosis. Acta Pharmacol Sin 2003; 24: 1259–64.

  12. 12

    Cheng Y, Shen LH, Zhang JT . Anti-amnestic and anti-aging effects of ginsenoside Rg1 and Rb1 and its mechanism of action. Acta Pharmacol Sin 2005; 26: 143–9.

  13. 13

    Zhang YG, Liu TP . Influences of ginsenosides Rb1 and Rg1 on reversible focal brain ischemia in rats. Acta Phammacol Sin 1996; 17: 44–8.

  14. 14

    Wang XY, Zhang JT . Effects of ginsenoside Rg1 on synaptic plasticity of freely moving rats and its mechanism of action. Acta Pharmacol Sin 2001; 22: 657–62.

  15. 15

    Wang XY, Zhang JT . NO mediates ginsenoside Rg1-induced long-term potentiation in anesthetized rats. Acta Pharmacol Sin 2001; 22: 1099–102.

  16. 16

    Xue JF, Liu ZJ, Hu JF, Chen H, Zhang JT, Chen NH . Ginsenoside Rb1 promotes neurotransmitter release by modulating phosphoryla-tion of synapsins through a cAMP-dependent protein kinase pathway. Brain Res 2006; 1106: 91–8.

  17. 17

    Chang Y, Huang WJ, Tien LT, Wang SJ . Ginsenosides Rg1 and Rb1 enhance glutamate release through activation of protein kinase A in rat cerebrocortical nerve terminals (synaptosomes). Eur J Pharmacol 2008; 578: 28–36.

  18. 18

    Jovanovic JN, Sihra TS, Nairn AC, Hemmings HC Jr, Greengard P, Czernik AJ . Opposing changes in phosphorylation of specific sites in synapsin I during Ca2+ -dependent glutamate release in isolated nerve terminals. JNeurosci 2001; 21: 7944–53.

  19. 19

    Bading H, Greenberg ME . Stimulation of protein tyrosine phosphorylation by NMDA receptor activation. Science 1991; 253: 912–4.

  20. 20

    Miyabe T, Miletic V . Multiple kinase pathways mediate the early sciatic ligation-associated activation of CREB in the rat spinal dorsal horn. Neurosci Lett 2005; 381: 80–5.

  21. 21

    Shaywitz AJ, Greenberg ME . CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem 1999; 68: 821–61.

  22. 22

    Impey S, Obrietan K, Storm DR . Making new connections: role of ERK/MAP kinase signaling in neuronal plasticity. Neuron 1999; 23: 11–4.

  23. 23

    Shalin SC, Hernandez CM, Dougherty MK, Morrison DK, Sweatt JD . Kinase suppressor of Ras1 compartmentalizes hippocampal signal transduction and subserves synaptic plasticity and memory formation. Neuron 2006; 50: 765–79.

  24. 24

    Impey S, Obrietan K, Wong ST, Poser S, Yano S, Wayman G, et al. Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB-dependent transcription and ERK nuclear translocation. Neuron 1998; 21: 869–83.

  25. 25

    Bito H, Takemoto-Kimura S . Ca2+/CREB/CBP-dependent gene regulation: a shared mechanism critical in long-term synaptic plasticity and neuronal survival. Cell Calcium 2003; 34: 425–30.

  26. 26

    Cohen-Matsliah SI, Brosh I, Rosenblum K, Barkai E . A novel role for extracellular signal-regulated kinase in maintaining long-term memory-relevant excitability changes. J Neurosci 2007; 27: 12 584–9.

  27. 27

    Gorosito SV, Cambiasso MJ . Axogenic effect of estrogen in male rat hypothalamic neurons involves Ca2+, protein kinase C, and extracellular signal-regulated kinase signaling. J Neurosci Res 2008; 86: 145–57.

  28. 28

    Girault JA, Valjent E, Caboche J, Hervé, D . ERK2: a logical AND gate critical for drug-induced plasticity? Curr Opin Pharmacol 2007; 7: 77–85.

  29. 29

    Valjent E, Caboche J, Vanhoutte P . Mitogen-activated protein kinase/extracellular signal-regulated kinase induced gene regulation in brain: a molecular substrate for learning and memory? Mol Neurobiol 2001; 23: 83–99.

  30. 30

    Kanaseki T, Ikeuchi Y, Sugiura H, Yamauchi T . Structural features of Ca2+/calmodulin-dependent protein kinase II revealed by electron microscopy. J Cell Biol 1991; 115: 1049–60.

  31. 31

    Tokumitsu H, Wayman GA, Muramatsu M, Soderling TR . Calcium/calmodulin-dependent protein kinase kinase: identification of regulatory domains. Biochemistry 1997; 36: 12 823–7.

  32. 32

    Shalin SC, Egli R, Birnbaum SG, Roth TL, Levenson JM, Sweatt JD . Signal transduction mechanisms in memory disorders. Prog Brain Res 2006; 157: 25–41.

  33. 33

    Bradley J, Finkbeiner S . An evaluation of specificity in activity-dependent gene expression in neurons. Prog Neurobiol 2002; 67: 469–77.

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Correspondence to Jun-tian Zhang or Nai-hong Chen.

Additional information

Project supported by Research Fund for the Doctoral Program of Higher Education (No 20070023075).

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  • ginsenoside Rg1
  • ERK1/2
  • CaMKIIα
  • CREB

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