Grant: Project Grant

alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type ionotropic glutamate receptors mediate most fast-excitatory neurotransmission in the developing and adult human brain. They form the hardwiring of most brain circuits but also strengthen or weaken them during periods of sustained patterned activity or altered homeostasis. AMPA receptors (AMPARs) are also implicated in numerous CNS disorders and thus are targeted for the development of clinically-relevant compounds. Consequently, there has been a concerted effort to provide a full understanding of the structural and functional aspects of AMPAR signaling. Recent work has identified a diverse family of auxiliary subunit proteins that bind to AMPARs and regulate their function. Since AMPAR auxiliary subunit complexes are expressed in different brain regions, it has been speculated that the selective targeting of each of these receptor complexes may be beneficial in developing therapeutic compounds with better specificity and fewer side-effects. In this grant application, we identify the unique binding pockets where several important families of auxiliary subunits interact with AMPARs. The proposed experiments will examine how each of these auxiliary proteins regulate AMPAR function and in turn, impact their signaling properties in neuronal circuits. We anticipate that this work will not only provide valuable insight into the molecular underpinnings of neuronal circuits that underlie human behavior but also provide insight into CNS disease.