Regulation of Na_V1.2 Channels by Brain-Derived Neurotrophic Factor, TrkB, and Associated Fyn Kinase

Abstract

Voltage-gated sodium channels are responsible for action potential initiation and propagation in neurons, and modulation of their function has an important impact on neuronal excitability. Sodium channels are regulated by a Src-family tyrosine kinase pathway, and this modulation can be reversed by specifically bound receptor phosphoprotein tyrosine phosphatase-␤. However, the specific tyrosine kinase and signaling pathway are unknown. We found that the sodium channels in rat brain interact with Fyn, one of four Src-family tyrosine kinases expressed in the brain. Na V 1.2 channels and Fyn are localized together in the axons of cultured hippocampal neurons, the mossy fibers of the hippocampus, and cell bodies, dendrites, and axons of neurons in many other brain areas, and they coimmunoprecipitate with Fyn from cotransfected tsA-201 cells. Coexpression of Fyn with Na V 1.2 channels decreases sodium currents by increasing the rate of inactivation and causing a negative shift in the voltage dependence of inactivation. Reconstitution of a signaling pathway from brain-derived neurotrophic factor (BDNF) to sodium channels via the tyrosine receptor kinase B (TrkB)/p75 neurotrophin receptor and Fyn kinase in transfected cells resulted in an increased rate of inactivation of sodium channels and a negative shift in the voltage dependence of inactivation after treatment with BDNF. These results indicate that Fyn kinase is associated with sodium channels in brain neurons and can modulate Na V 1.2 channels by tyrosine phosphorylation after activation of TrkB/p75 signaling by BDNF.

An antinociceptive role for substance P in acid-induced chronic muscle pain

“…None of these SP-induced currents required the direct participation of G proteins, but both depended on PTK. That SP antinociception in muscle acts via an Src kinase is intriguing because Src kinases can be activated downstream of the neurotrophin receptor (46,47). Given that i.m.…”

Effects of Sciatic Nerve Axotomy on Excitatory Synaptic Transmission in Rat Substantia Gelatinosa

“…Although this apparent discrepancy may be conveniently ascribed to the use of expression systems in some studies (Ahn et al 2007;Colley et al 2007), and to differential effects of acutely and chronically applied BDNF, a 2-h application of this neurotrophin has been reported to promote a marked increase in excitability of auditory brain stem neurons (Youssoufian and Walmsley 2007). Long-term application of BDNF, however, does not exert much effect on Na ϩ channels in primary afferent neurons (Oyelese et al 1997).…”

Functional Interaction between the Scaffold Protein Kidins220/ARMS and Neuronal Voltage-Gated Na+ Channels

“…Time constants were determined by fitting the current decay at Ϫ20 mV (upon step depolarization for 150 ms) with a double-exponential function. (31)(32)(33)(34), some specifically concern Na v channels: Na v 1.2 channels are subject to dynamic regulation by tyrosine phosphorylation/dephosphorylation events, with Fyn kinase acting to increase fast inactivation in response to TrkB activation (20,35) and the tyrosine phosphatase RPTP␤ having the opposite effect (36). Furthermore, BDNF (in complex with TrkB receptors) has been proposed to elicit the rapid activation of Na v 1.9 channels, which appears to occur in a ligand-gated rather than in a voltage-gated manner (37).…”

“…The specific channel localization is determined by the interaction of ␣ and ␤ subunits with a set of adhesion molecules, as well as cytoskeletal and extracellular matrix proteins (17,18). Na v channel activity is modulated by the coordinated activation of several signaling pathways, being targets of phosphorylation by protein kinase A (19) and by Fyn kinase acting downstream of the BDNF-TrkB complex (20). Despite the vast amount of data available in the literature, however, the network of signaling events controlling Na v channel localization and activity is still far from being completely understood.…”