Dysregulation of cell excitability contributes to many debilitating and/or life-threatening medical conditions, including cardiac arrhythmias, epilepsy, anxiety, depression, schizophrenia, Down Syndrome, addiction, and pain. Work in our lab seeks to better understand molecules and mechanisms that control excitability, so that safer and more effective strategies can be developed to treat these afflictions. Our recent work has focused on the G protein-gated inwardly-rectifying potassium channel, or GIRK channel, a key mediator of cell excitability in the heart and central nervous system. GIRK channels mediate the impact of the parasympathetic nervous system on heart rate and arrhythmogenesis. They also play key roles in pain perception, addiction, cognition, and mood. Our ongoing funded projects are directed at identifying molecules and mechanisms that modulate GIRK channel activity in neurons and cardiac myocytes, elucidating roles for GIRK channels in mood-related behavior and cognition, understanding experience- and drug-induced plasticity of GIRK-dependent signaling in the context of addiction, and evaluating the efficacy of novel small-molecular modulators of GIRK channels in preclinical studies of mood, pain, and cognitive dysfunction.