Speaker : Jin Sung Choi (Assistant Professor, The Catholic University of Korea)

Date : 2011-12-13

Location : Room 108，Pharmacy Hall, Dankook University

Abstract : Nav1.7 sodium channels can amplify weak stimuli in neurons and act as a threshold channel for firing action potentials. Neurotrophic factors and pro-nociceptive cytokines are released during development and under pathological conditions activate mitogen-activated protein kinases (MAPK). MAP kinases transduce the signal by regulating transcription factors thus initiating a gene expression response, a long-term effect, and directly modulate neuronal ion channels including sodium channels, thus acutely regulating DRG neuron excitability. For example, neurotrophic growth factor (NGF) activates (phosphorylates) ERK1/2 MAPK, PERK1/2, in DRG neurons, an effect which has been implicated in injury-induced hyperalgesia. However, the acute effects of PERK1/2 on sodium channels are not known. We have previously shown that activated p38 MAPK, pp38, directly phosphorylates Nav1.6 and Nav1.8 sodium channels and regulates their current densities without altering their gating properties. We now report that acute activation of ERK1/2 regulates resting membrane potential and firing properties of DRG neurons. We also show that PERK1/2 induces a hyperpolarizing shift of activation and fast-inactivation of Nav1.7 without altering current density, unlike the effect of pp38 on Nav1.6 and Nav1.8, and we demonstrate that this effect is mediated by the direct phosphorylation of specific residues within the first intracellular loop of the channel. Thus direct phosphorylation and modulation of Nav1.7 by PERK1/2 contribute to the effect of these kinases on DRG neuron excitability.