Structural Pharmacology of GIRK Channel Disease Mutants

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

Abstract

Summary Several human diseases are caused by mutations in potassium channels (channelopathies) that are either loss- or gain-of-function. Missense mutations in KCNJ6 (GIRK2) have been linked to Keppen-Lubinsky Syndrome (KLS), a disorder characterized by lipodystrophy, severe developmental delay, intellectual disability, hypertonia, hyperreflexia and growth retardation. GIRK2 is a member of the GIRK channel family, which includes inwardly rectifying potassium (Kir) channels that are activated by G proteins. Activation of GIRK channels hyperpolarize neurons leading to reduced neuronal activity. Mutations in human GIRK2 (T152, G154S/C, L171R) have been identified in KLS, with each mutation leading to a loss of K+ selectivity and aberrant constitutive activation. However, the structural mechanisms underlying the change in ion selectivity and gating with KLS mutations in GIRK2 are poorly understood. These changes in channel properties convert GIRK2 from inhibitory to strongly excitatory (gain-of-function), contributing to the severe neuropathology and neurological changes observed in KLS patients. Currently, there are no treatments that target these channels, and current FDA approved drugs are inadequate for treating for KLS patients. We propose to elucidate the molecular mechanisms underlying the loss of K+ selectivity and G protein-independent activity with GIRK2 KLS mutations. We will then identify and characterize novel inhibitors specific for GIRK2 KLS channels using virtual docking and functional assays. In addition, little is known about the functional consequence of GIRK2 KLS channels expressed in human neurons. We will develop a human cell-based model of KLS using hiPSC-derived neurons that co-express GIRK2 KLS channels. Using these KLS neurons, we will evaluate the potential therapeutic effect of GIRK2 channel inhibitors on neuronal function. To carry out these aims, our team implements a multi-disciplinary approach, combining high-resolution channel structures (CryoEM), computational docking, drug development, and human neurons. Identification of a selective inhibitor of the KLS channels could provide the foundation for developing a novel treatment. If substantiated, our approach of identifying novel channel inhibitors would be transformative in treating neurological disorders caused by mutant potassium channels as well as other ion channels.