Pain is a major global health problem, costing an estimated $100 billion in the United States alone each year. A lack of full understanding of the cellular and molecular mechanisms contributing to pain leads to an unmet medical need for the treatment. While voltage-gated sodium channels are mainly responsible for the depolarizing phase of action potentials, resurgent sodium current evoked during repolarization is essential to promoting high-frequency neuronal firing and contributes to hyperexcitability of nociceptive neurons. The sodium channel auxiliary subunit Nav?4 is believed to play a vital role in resurgent current generation. Aberrant Nav?4-mediated resurgent current has been linked extensively to multiple human painful diseases. However, Nav?4 knockout only partially reduces resurgent current, suggesting the existence of unknown key molecular mechanisms. Three sodium channel isoforms (Nav1.7, Nav1.8 and Nav1.9) are predominantly and almost exclusively expressed in nociceptive neurons. Nav1.8 is particularly shown to play an absolutely crucial role in pain sensation, including chronic neuropathic pain. Nav1.8 also has been considered as an ideal target for developing drugs to increase the therapeutic armamentarium for pain. In this project, we are proposing a novel mechanism of resurgent current generation independent of Nav?4, by which the resurgent current is required for nociceptive neurons to maintain high-frequency firing. The novel resurgent current is directly mediated by fibroblast growth factor homologous factors (FHFs), a family of intracellular proteins having a long N-terminus. FHFs are widely co-localized with sodium channels throughout developing and adult CNS and PNS.
Two specific aims are proposed:
AIM I will determine if FHFs serve as critical mediators of Nav1.8 resurgent current.
AIM II will determine the impacts of FHF-mediated Nav1.8 resurgent current on pain behaviors. Although we initially target Nav1.8 channels in DRG neurons because of their importance in pain, this novel mechanism can be easily applicable to other sodium channel isoforms that interact with these FHFs. Therefore this will help us to better understand and target resurgent currents and provide a promising therapeutic target for the treatment of pain.
Pain is a major global health problem that is difficult to treat in many patients. There is exceptionally strong experimental and clinical evidence indicating that subtle changes in the properties of Nav1.8 can substantially influence excitability of nociceptive sensory neurons, therefore altering pain sensations. This study discovers a family of novel proteins that may mediate Nav1.8 resurgent current contributing to pain sensation.
