Neuronal G protein-gated inwardly rectifying K+ (GIRK) channels mediate the postsynaptic inhibitory effect of many neurotransmitters and related drugs of abuse. The long-term goal of my research is to understand how GIRK channels shape behaviors associated with specific neurotransmitter signaling pathways. To accomplish this objective, we need to understand the functional implications of native GIRK channel diversity, and we need to develop the means to perturb GIRK channels with molecular precision. Accordingly, the goal of this proposal is to determine how subunit composition influences interactions between GIRK channels and related signaling molecules. Our working hypothesis is that subunit composition dictates interactions between GIRK channels and neuronal proteins that facilitate coupling with appropriate G protein-coupled receptors. The working hypothesis will be tested with cell biological, biochemical, electrophysiological, and behavioral experiments that examine the robust coupling between GIRK channels and the GABAB receptor. We will exploit the existence of a powerful set of mouse knockout lines and custom-derived antibodies to identify structural elements promoting robust functional interactions between GIRK2-containing channels and GABAB receptors (AIM #1), to determine how GIRK channel subunit composition influences interactions with endogenous neuronal proteins (AIM #2), and to examine how subunit composition influences the contribution of GIRK channels to the behavioral effects of GABAB receptor activation (AIM #3). While addressing issues related to GIRK channels and G protein signaling that have been refractory to standard recombinant approaches, the proposed research will also suggest novel points of intervention for the selective perturbation of signaling involving GABAB receptors and/or GIRK channels. In the context of GABAB-dependent signaling, such progress could translate into novel therapies for the treatment of epilepsy, pain, and addiction. Relevance to public health. All drugs used to treat human disease or distress produce both beneficial and untoward effects. The premise of the work presented in this application is that the beneficial effects of many drugs could be emphasized, or the negative effects suppressed, if we understood better the molecular mechanisms underlying the complex physiological and behavioral responses to drug administration.