Kinase-mediated regulation of ion channels is central to numerous cellular signaling pathways, yet the molecular underpinnings of these protein-protein interactions (PPIs) remain incompletely defined. Here, we present ongoing biophysical studies aimed at elucidating the interaction mechanisms between a key kinase, glycogen synthase kinase 3 β (GSK3β), and its target ion channel, voltage-gated sodium channel 1.6 (Nav1.6). Dysregulation of Nav1.6 and overexpression of GSK3β have been directly linked to network hyperexcitability, a hallmark of early-stage Alzheimer's disease and other neuropsychiatric disorders. Utilizing a combination of biochemical and functional assays—including surface plasmon resonance (SPR), split-luciferase complementation assay (LCA), chemoinformatics, kinase assays, and electrophysiology—we are characterizing the affinity, dynamics, and conformational consequences of their association. Furthermore, we leverage a proprietary library of small molecule MZ compounds, derived from the known 1063 compound, to probe and modulate the GSK3β/Nav1.6 PPI. Our preliminary findings offer new insights into the regulatory principles governing these complexes, revealing dynamic adaptability that may be relevant to signaling networks. This work provides a platform for understanding the structural determinants of kinase-ion channel modulation and sets the stage for future functional and therapeutic explorations aimed at neurodegenerative and neuropsychiatric disorders.
Gurtu et al. (Sun,) studied this question.