Voltage-gated sodium channels are critical determinants of neuronal and muscle cellular excitability. These channels may also play a crucial role in chronic pain, epilepsy and other neurological disorders. However, investigations into the precise functional role that specific sodium channel isoforms play in normal and abnormal cellular excitability is lacking. A main objective of our research is to identify molecular mechanism(s) underlying alterations in the electrical excitability of sensory neurons. Experimental and clinical studies have clearly shown that the peripheral nerve fibers, and the neuronal cell bodies that give rise to them, can become hyperexcitable after injury and that this hyperexcitability contributes to neuropathic pain. Changes in sodium currents are likely to alter the excitability of sensory neurons, and could contribute to the reduced threshold for repetitive firing and increased level of spontaneous firing that has been observed in injured and inflamed sensory neurons. Subthreshold sodium currents, currents that are active at membrane potentials negative to the threshold for action potential generation, can play crucial roles in regulating electrogenesis in neurons. The present proposal focuses on tetrodotoxin-sensitive subthreshold sodium currents in sensory neurons and their role in chronic pain mechanisms. This project will address the hypothesis that altered sodium currents play a crucial role in the development of enhanced excitability associated with chronic pain with the following specific aims: 1. Characterize the properties of sodium currents in cutaneous afferent dorsal root ganglion neurons acutely isolated from normal adult rats, after chronic peripheral inflammation and after peripheral nerve injury. 2. Determine how specific sodium channel isoforms contribute to sodium currents in control and sensitized neurons. 3. Examine the effect of sodium channel mutations that cause the inherited painful neuropathy primary erythermalgia in humans on Nav1.7 sodium channel properties and excitability in sensory neurons. Understanding the changes that occur in the sodium currents of sensory neurons following inflammation and/or nerve injury and how specific sodium channel isoforms contribute to these changes should enhance our understanding of the normal and abnormal physiology of sensory neurons and should aid the development of new therapeutic strategies for the treatment of pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS053422-05
Application #
7744613
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Stewart, Randall R
Project Start
2006-01-19
Project End
2011-06-30
Budget Start
2010-01-01
Budget End
2011-06-30
Support Year
5
Fiscal Year
2010
Total Cost
$293,617
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pharmacology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Shugg, Tyler; Johnson, Derrick E; Shao, Minghai et al. (2018) Calcium/calmodulin-dependent protein kinase II regulation of IKs during sustained ?-adrenergic receptor stimulation. Heart Rhythm 15:895-904
Barbosa, Cindy; Xiao, Yucheng; Johnson, Andrew J et al. (2017) FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons. Pflugers Arch 469:195-212
Ohlemacher, Sarah K; Sridhar, Akshayalakshmi; Xiao, Yucheng et al. (2016) Stepwise Differentiation of Retinal Ganglion Cells from Human Pluripotent Stem Cells Enables Analysis of Glaucomatous Neurodegeneration. Stem Cells 34:1553-62
Xie, Wenrui; Tan, Zhi-Yong; Barbosa, Cindy et al. (2016) Upregulation of the sodium channel NaV?4 subunit and its contributions to mechanical hypersensitivity and neuronal hyperexcitability in a rat model of radicular pain induced by local dorsal root ganglion inflammation. Pain 157:879-91
Pei, Zifan; Xiao, Yucheng; Meng, Jingwei et al. (2016) Cardiac sodium channel palmitoylation regulates channel availability and myocyte excitability with implications for arrhythmia generation. Nat Commun 7:12035
Patel, Reesha R; Barbosa, Cindy; Brustovetsky, Tatiana et al. (2016) Aberrant epilepsy-associated mutant Nav1.6 sodium channel activity can be targeted with cannabidiol. Brain 139:2164-81
Torregrosa, Robert; Yang, Xiao-Fang; Dustrude, Erik T et al. (2015) Chimeric derivatives of functionalized amino acids and ?-aminoamides: compounds with anticonvulsant activity in seizure models and inhibitory actions on central, peripheral, and cardiac isoforms of voltage-gated sodium channels. Bioorg Med Chem 23:3655-66
Barbosa, Cindy; Tan, Zhi-Yong; Wang, Ruizhong et al. (2015) Nav?4 regulates fast resurgent sodium currents and excitability in sensory neurons. Mol Pain 11:60
Patel, Reesha R; Barbosa, Cindy; Xiao, Yucheng et al. (2015) Human Nav1.6 Channels Generate Larger Resurgent Currents than Human Nav1.1 Channels, but the Nav?4 Peptide Does Not Protect Either Isoform from Use-Dependent Reduction. PLoS One 10:e0133485
Chen, Xingjuan; Sun, Weiyang; Gianaris, Nicholas G et al. (2014) Furanocoumarins are a novel class of modulators for the transient receptor potential vanilloid type 1 (TRPV1) channel. J Biol Chem 289:9600-10

Showing the most recent 10 out of 44 publications