Insulin-like growth factor-1 receptor-mediated inhibition of A-type K(+) current induces sensory neuronal hyperexcitability through the phosphatidylinositol 3-kinase and extracellular signal-regulated kinase 1/2 pathways, independently of Akt

Endocrinology. 2014 Jan;155(1):168-79. doi: 10.1210/en.2013-1559. Epub 2013 Dec 20.


Although IGF-1 has been implicated in mediating hypersensitivity to pain, the underlying mechanisms remain unclear. We identified a novel functional of the IGF-1 receptor (IGF-1R) in regulating A-type K(+) currents (IA) as well as membrane excitability in small trigeminal ganglion neurons. Our results showed that IGF-1 reversibly decreased IA, whereas the sustained delayed rectifier K(+) current was unaffected. This IGF-1-induced IA decrease was associated with a hyperpolarizing shift in the voltage dependence of inactivation and was blocked by the IGF-1R antagonist PQ-401; an insulin receptor tyrosine kinase inhibitor had no such effect. An small interfering RNA targeting the IGF-1R, or pretreatment of neurons with specific phosphatidylinositol 3-kinase (PI3K) inhibitors abolished the IGF-1-induced IA decrease. Surprisingly, IGF-1-induced effects on IA were not regulated by Akt, a common downstream target of PI3K. The MAPK/ERK kinase inhibitor U0126, but not its inactive analog U0124, as well as the c-Raf-specific inhibitor GW5074, blocked the IGF-1-induced IA response. Analysis of phospho-ERK (p-ERK) showed that IGF-1 significantly activated ERK1/2 whereas p-JNK and p-p38 were unaffected. Moreover, the IGF-1-induced p-ERK1/2 increase was attenuated by PI3K and c-Raf inhibition, but not by Akt blockade. Functionally, we observed a significantly increased action potential firing rate induced by IGF-1; pretreatment with 4-aminopyridine abolished this effect. Taken together, our results indicate that IGF-1 attenuates IA through sequential activation of the PI3K- and c-Raf-dependent ERK1/2 signaling cascade. This occurred via the activation of IGF-1R and might contribute to neuronal hyperexcitability in small trigeminal ganglion neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Membrane / metabolism
  • Electrophysiology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Immunohistochemistry
  • Insulin-Like Growth Factor I / metabolism
  • Male
  • Mice
  • Mice, Inbred ICR
  • Neurons / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Potassium / chemistry
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Proto-Oncogene Proteins c-raf / metabolism
  • Receptor, IGF Type 1 / metabolism*
  • Shaker Superfamily of Potassium Channels / metabolism*
  • Signal Transduction*
  • Trigeminal Ganglion / metabolism


  • Shaker Superfamily of Potassium Channels
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinases
  • Receptor, IGF Type 1
  • Akt1 protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-raf
  • Extracellular Signal-Regulated MAP Kinases
  • Potassium