Novel modulation of AMPA receptor activity by ly-6 proteins
Initial Award Abstract
Glutamate receptors are proteins that mediate communication between neurons in the brain. Abnormal glutamate receptor activity has been linked to neurological disorders such as Parkinson’s disease, epilepsy, stroke and chronic pain. Long-term nicotine exposure, such as that experienced by smokers, has been shown to increase glutamate receptor activity in areas of the brain implicated in addiction and drug-seeking behaviors, thus leading to the hypothesis that these behaviors may be ameliorated by antagonizing glutamate receptor function. The processes that lead to upregulation of glutamate receptors by chronic nicotine exposure are unknown, but may be driven by molecules that bind to and regulate glutamate receptor activity.
In this proposal I will demonstrate that certain proteins belonging to the ly-6 family meet these two criteria. I will demonstrate that specific ly-6 proteins form complexes with and regulate the functions of glutamate receptors, and I will determine the mechanisms by which this regulation occurs. I will also determine the effect of chronic nicotine exposure (mimicking conditions in a smoker’s brain) on ly-6-mediated regulation of receptor activity. Glutamate receptors present a highly novel target for developing potential therapeutics to treat symptoms of nicotine addiction and withdrawal, as the bulk of the work in the field has focused on another family of receptors, the nicotinic acetylcholine receptors.
The work described in this proposal will lay the groundwork for a vibrant research program to continue to identify and characterize the ly-6 proteins as novel modulators of glutamate receptors, with the potential to enhance our understanding of glutamate receptor function, inform future studies on ly-6 mediated modulation of other ion channels of therapeutic interest, and facilitate the development of novel therapies for treating nicotine addiction and/or attenuate nicotine-seeking behaviors.