Functional mechanisms and therapeutic potential of EAG channel regulators

Ether-a-go-go (EAG) potassium selective channels are important regulators of neuronal
excitability and cancer progression. Defects in EAG channel function are associated
with neurological disorders and cancer. Despite the physiological importance of EAG
channels, molecular mechanisms of EAG channel regulation by intracellular ligands and
clinically relevant EAG channel regulators are not known. The goal of this proposal is to
uncover molecular mechanisms of EAG channel regulation by intracellular ligands
recently discovered by our laboratory and to determine a therapeutic potential of these
ligands for treatment of diseases linked to EAG channels. In Specific Aim 1 we plan to
solve X-ray structures of the intracellular Per-Arnt-Sim (PAS) and cyclic nucleotide-
binding homology (CNBH) domains of EAG channels bound to the recently identified
ligands and conduct computational simulations of the ligand binding to the PAS and
CNBH domains to uncover the structural basis of EAG channel regulation by the
intracellular ligands. The structural findings will be then used as a road map to guide
functional experiments on the molecular mechanisms of EAG channel regulation by the
ligands. In Specific Aim 2 we plan to use surface plasmon resonance method to identify
novel EAG channel ligands that affect channel function through PAS and CNBH domain
interface. We will then use electrophysiology to determine functional implications of
strengthening or weakening of the PAS/CNBH domain interface by the identified
regulators on the function of EAG channels. In Specific Aim 3 we plan to use tissue
culture and zebrafish xenograft models to test therapeutic potential of the identified
regulators for treatment of cancer. The results of these studies will be crucial for
understanding fundamental regulatory mechanisms of EAG and related ERG and ELK
channels, and for attaining therapeutic potential of EAG channel regulators.

Grant Number: 5R01CA252969-05
NIH Institute/Center: NIH
Principal Investigator: Tinatin Brelidze