Altered PKA modulation in the Na_v1.1 epilepsy variant I1656M

Abstract

lepsy with febrile seizures plus (GEFS ϩ ) is an inherited epilepsy that can result from mutations in at least four ion channel subunits. The majority of the known GEFS ϩ mutations have been identified in SCN1A, the gene encoding Na v 1.1 ␣-subunit. Protein kinases as critical modulators of sodium channels have been closely related to the genesis of epilepsy. However, little is known about how protein kinases affect the GEFS ϩ mutant sodium channel. To gain insight into the protein kinases effect on channel properties and neuronal excitability of SCN1A mutant channels, we investigated the human SCN1A GEFS ϩ mutation I1656M by using whole cell patch-clamp technique and an established computational neuron model. The results showed that the PKA inhibition of sodium current amplitude significantly decreased in the I1656M mutant channels, but the PKC inhibition did not. The responses of the voltage-dependent activation and fast inactivation to PKA activator disappeared in the I1656M mutant channels, but the response of the voltage dependence of the slow inactivation did not. Computational model analysis suggested that changes of the I1656M mutant channel gating behaviors in response to PKA activation altered neuronal excitability. These results indicate that altered responses of the mutant channels to PKA signaling may impair the delicate balances between chemical and electrical harmony and lead to abnormal neuronal excitability.

Cerebellar Stellate Cell Excitability Is Coordinated by Shifts in the Gating Behavior of Voltage-Gated Na+and A-Type K+Channels

“…Much less is known about the regulation of Nav1.1 channels, although, earlier recombinant studies and more recent proteomic work has identified putative phosphorylation sites which often overlap with sites identified for Nav1.2 channels (Smith and Goldin, 1998; Berendt et al, 2010). Interestingly, forskolin activation of PKA causes a hyperpolarizing shift in both the activation and inactivation curves for recombinant Nav1.1 (Liu and Zheng, 2013) as observed in the present study on cerebellar SCs. An identical gating shift is observed in hippocampal CA1 pyramidal cells, probably mediated by Nav1.2 channels, that is triggered by NMDA receptor activation and the activity of CaM kinase II (Xu et al, 2005).…”

Post-translational modifications of voltage-gated sodium channels in chronic pain syndromes

“…This suggests that both the function and expression of Na v 1.2 are modified by PKA. Since these early studies, other groups have reported similar decreases in Na v 1.1, Na v 1.6, and Na v 1.7 in different cell expression systems and intact cells ( Gershon et al, 1992 ; Cantrell et al, 1997 ; Smith and Goldin, 1998 ; Zhou et al, 2000 ; Vijayaragavan et al, 2004a ; Chen et al, 2008 ; Liu and Zheng, 2013 ). The phosphorylation sites of Na v 1.2 by PKA were mostly investigated using traditional biochemical approaches ( Murphy et al, 1993 ; Smith and Goldin, 1996 ; Cantrell et al, 1997 ).…”

C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system

“…Increasing cytosolic cyclic AMP concentration results in activation of protein kinase A (PKA), which we found in the nodal region, and other intracellular pathways [32,33]. Through kinase activation, CGRP could regulate ion channels essential for nerve signal propagation [34][35][36] and contribute to mechanisms of neural sensitization and/or increased intensity of pain transmission in migraine. Nodes of Ranvier are complex, highly organized structures in which the central, unmyelinated portion of the node itself is flanked by paranodal and juxtaparanodal regions [15].…”