FHF2A and FHF2B in sensory neurons: potential regulators of resurgent currents

Barbosa Nunez, Cindy

Abstract

Pain is one of the most prevalent reasons people in the US seek medical care. Although it is well known that hyperexcitability of dorsal root ganglion (DRG) sensory neurons can contribute to neuropathic and inflammatory pain, the cellular and molecular changes that underlie this hyperexcitability are not fully understood. This lack of knowledge has hindered the development of better therapeutics. One mechanism that clearly contributes to pain is increased electrical activity in DRG containing peripheral sensory neurons. Voltage gated sodium channels (VGSC) contribute to the excitability of sensory neurons, as they are essential for the upstroke of the action potential. A unique type of VGSC current, resurgent current, generates an inward current at repolarizing voltages through an alternate mechanism of inactivation termed open channel block. Resurgent currents are thought to contribute to spontaneous firing, hyperexcitability and the initiation of pain sensations in DRG sensory neurons. Increased resurgent currents in sensory neurons have been implicated in Paroxysmal Extreme Pain Disorder (PEPD), sea-anemone toxin ATX-II induced pain, and oxaliplatin acute- cooling aggravated painful neuropathy. Unfortunately, our understanding of the molecular mechanisms that underlie resurgent currents, especially in DRG neurons, is poor. We propose that Fibroblast Growth Factor Homologous Factors (FHF) 2 that bind the C-terminus of VGSC can substantially modulate resurgent currents in sensory neurons. Specifically, we hypothesize that FHF2A limits resurgent current generation in sensory neurons by mediating long-term inactivation and that FHF2B enhances resurgent currents generation by modulating the voltage dependence of inactivation. Therefore in this NRSA fellowship the applicant will: 1) knockdown FHF2A protein expression and use an antibody targeted to the N-terminus of FHF2A to determine the functional effect on resurgent current generation, 2) overexpress FHF2A to determine if increasing FHF2A activity reduces resurgent currents and 3) knockdown FHF2B protein expression and overexpress FHF2B to determine if modulation this variant enhances resurgent currents. We will also measure endogenous levels of FHF2A and FHF2B in DRG neurons tested for resurgent current to assess correlations between expression profiles and resurgent current properties. The results of this proposal should help us identify novel approaches for the study of hyperexcitability associated with increased resurgent currents, and aid the development of treatments for painful conditions such as PEPD, acute oxaliplatin-induced painful neuropathy and possibly inflammatory pain.

Public Health Relevance

Pain is a serious health problem for which currently available treatments are often not fully effective or are limited by side effects. We have identified a novel mechanism in pain sensing neurons that likely contributes to abnormal pain. Identifying the molecules and mechanisms underlying problematic pain sensations will enhance our ability develop new strategies for treating pain.