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

Although IGF-1 has been implicated in mediating hypersensitivity to pain, the underlying mechanisms remain unclear. Weidentified a novel functional of the IGF-1 receptor (IGF-1R) in regulating A-type K+ currents (z) as well as membrane excitability in small trigeminal ganglion neurons. Our results showed that IGF-1 reversibly decreased I-A, whereas the sustained delayed rectifier K+ current was unaffected. This IGF-1-induced I-A 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 I-A decrease. Surprisingly, IGF-1-induced effects on I-A 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 I-A 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 I-A 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.