Paul Wadsworth
Targeting Protein: Protein Interactions at the Voltage Gated Sodium Channel Complex for Pharmacologic Development\
Summary
As fundamental determinants of neuronal function, voltage-gated Na+ (Nav) channels are important targets for therapeutic development against a wide range of health conditions. Dysfunction of Nav channels in the CNS is associated with disorders ranging from neurological (i.e., epilepsy) to psychiatric (i.e., major depression disorder). Unfortunately, commercially available drugs targeting Nav channels are largely non-specific, giving rise to severe side effects such as movement disorders. Thus, there is an unmet need for discovering new therapeutically relevant probes and pathways. Recent evidence suggests that protein:protein interactions (PPI) between Nav channels and their accessory proteins play a key role in regulating neuronal firing, and that minimal disturbances to these tightly controlled PPI can lead to persistent maladaptive plasticity. These PPI interfaces are highly specific and provide ideal targets for drug development, especially in the CNS, where selectivity and specificity are vital for limiting side effects. Therefore, the goal of the present study was to develop a screening platform capable of identifying new regulators of the Nav channel complex. Specifically, the project focused on the PPI between Nav1.6 and its regulatory protein, FGF14. Beginning with a newly developed series of cellbased assays, this research discovered a mechanism by which the JAK2 tyrosine kinase might directly influence neuronal firing through phosphorylation of FGF14. Furthermore, a high-throughput screening of ~45,000 small molecules was conducted, identifying two potent modulators of the FGF14:Nav1.6 complex that are functionally active and predicted to be permeable to the blood-brain barrier. While providing a robust in-cell screening platform that can be adapted to search for any channelopathyassociated regulatory protein, these results lay the potential groundwork for a new class of drugs targeting Nav channels with a broad range of applicability for CNS disorders/
Since embarking on my graduate studies, I have been intrigued by the idea of defining new drug targets for the treatment of CNS disorders. The PhRMA Foundation Fellowship in Pharmacology/Toxicology, through its commitment to providing comprehensive training in drug development, has enabled me to devote all my efforts toward impactful research in neuropsychopharmacology and fostered my development as a physician-scientist.
