TRPC6 channel-mediated neurite outgrowth in PC12 cells and hippocampal neurons involves activation of RAS/MEK/ERK, PI3K, and CAMKIV signaling

J Neurochem. 2013 Nov;127(3):303-13. doi: 10.1111/jnc.12376. Epub 2013 Aug 19.


The non-selective cationic transient receptor canonical 6 (TRPC6) channels are involved in synaptic plasticity changes ranging from dendritic growth, spine morphology changes and increase in excitatory synapses. We previously showed that the TRPC6 activator hyperforin, the active antidepressant component of St. John's wort, induces neuritic outgrowth and spine morphology changes in PC12 cells and hippocampal CA1 neurons. However, the signaling cascade that transmits the hyperforin-induced transient rise in intracellular calcium into neuritic outgrowth is not yet fully understood. Several signaling pathways are involved in calcium transient-mediated changes in synaptic plasticity, ranging from calmodulin-mediated Ras-induced signaling cascades comprising the mitogen-activated protein kinase, PI3K signal transduction pathways as well as Ca(2+) /calmodulin-dependent protein kinase II (CAMKII) and CAMKIV. We show that several mechanisms are involved in TRPC6-mediated synaptic plasticity changes in PC12 cells and primary hippocampal neurons. Influx of calcium via TRPC6 channels activates different pathways including Ras/mitogen-activated protein kinase/extracellular signal-regulated kinases, phosphatidylinositide 3-kinase/protein kinase B, and CAMKIV in both cell types, leading to cAMP-response element binding protein phosphorylation. These findings are interesting not only in terms of the downstream targets of TRPC6 channels but also because of their potential to facilitate further understanding of St. John's wort extract-mediated antidepressant activity. Alterations in synaptic plasticity are considered to play an important role in the pathogenesis of depression. Beside several other proteins, TRPC6 channels regulate synaptic plasticity. This study demonstrates that different pathways including Ras/MEK/ERK, PI3K/Akt, and CAMKIV are involved in the improvement of synaptic plasticity by the TRPC6 activator hyperforin, the antidepressant active constituent of St. John's wort extract.

Keywords: TRPC6 channels; calcium; hyperforin; neuritic outgrowth; synaptic plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Blotting, Western
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / physiology
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4 / physiology*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Enzyme Activation / drug effects
  • Enzyme-Linked Immunosorbent Assay
  • Extracellular Signal-Regulated MAP Kinases / physiology
  • Genes, ras / physiology*
  • Hippocampus / drug effects
  • Hippocampus / physiology*
  • MAP Kinase Signaling System / physiology
  • Neurites / drug effects
  • Neurites / physiology*
  • Neurons / physiology*
  • Oncogene Protein v-akt / physiology
  • PC12 Cells
  • Phloroglucinol / analogs & derivatives
  • Phloroglucinol / pharmacology
  • Phosphatidylinositol 3-Kinases / physiology*
  • Phosphorylation
  • Primary Cell Culture
  • Rats
  • TRPC Cation Channels / drug effects*
  • TRPC Cation Channels / physiology*
  • Terpenes / pharmacology


  • Anti-Bacterial Agents
  • Cyclic AMP Response Element-Binding Protein
  • TRPC Cation Channels
  • Terpenes
  • Trpc6 protein, rat
  • Phloroglucinol
  • Phosphatidylinositol 3-Kinases
  • Oncogene Protein v-akt
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4
  • Camk4 protein, rat
  • Extracellular Signal-Regulated MAP Kinases
  • hyperforin