Dysfunction of neostriatal dopaminergic signaling pathways has been implicated in a variety of neurobiological disorders. To understand the role dopamine plays within the neostriatum, it is crucial to delineate the second messenger systems and target proteins that are affected by dopamine receptor activation. This proposal outlines a series of experiments which will determine the actions of D1- and D2-class dopamine receptor stimulation on the neostriatal inwardly rectifying potassium channels, IRKs and GIRKs. Current passing through these channels tends to stabilize a cell close to the K+ equilibrium potential and as such, modulation of these channels will have significant impact on cell excitability. While physiologically crucial, up until recently, experiments attempting to isolate the inward rectifier in mammalian neurons ha failed. With much excitement, we have recently applied a successful strategy to isolate inward rectifier currents, and have begun to characterize the effect of D1 dopamine receptor stimulation on these conductances. The experiments listed in this proposal have been divided into the framework of three specific aims. (1) To isolate and characterize the inwardly rectifying K+ currents found in neostriatal neurons. (2) To correlate differences in the inwardly rectifying K+ current to the expression of IRK- and GIRK-class proteins. (3)To determine the effect of D1- and D2-class dopamine receptor stimulation on these inwardly rectifying currents.
