Early-onset Benign Familial Neonatal Epilepsy (BFNE) and Epileptic Encephalopathy (EE), are associated with mutations in neuronal KCNQ/Kv7 channel subunits Kv7.2 and Kv7.3. Kv7 channels are voltage-dependent potassium channels. Enriched at the axonal plasma membrane, they pump potassium ions out of the neurons and inhibit repetitive or burst firing of action potentials. A single neuronal Kv7 channel is a heterotetramer composed of two Kv7.2 and two Kv7.3 subunits. BFNE and EE mutations in Kv7.2 and Kv7.3 lead to decreased surface expression along the axon, which means less potassium ions are moved across the axonal membrane where action potentials are generated and propagated. This prevents the neuron from returning to its resting potential and allows repetitive action potentials indicative of a seizure.
The purpose of this project is to uncover the molecular mechanism by which Kv7 channels are targeted to the axonal surface and enriched at the axonal initial segment (AIS). Since epilepsy mutations in Kv7 channels reduce this axonal targeting, understanding the mechanism underlying axonal targeting could provide therapeutic targets to treat epilepsy. Two motor proteins KIF3A and KIF5B are shown to target other potassium channels such as Kv1 to the axon. Here, we are investigating to test if overexpression of KIF3A and KIF5B proteins will lead to increased surface expression of neuronal Kv7 channels in the axon of hippocampal neurons
