The coordination and regulation of electrical signals across excitable cells is a complex, dynamic phenomenon requiring, in part, the interaction of ion channels with cellular constituents. The intracellular loops or domains of many ion channel subunits have been shown to specifically bind other cellular components that act in receptor targeting, localization, regulation, or modulation of function. In this report we describe experiments in which the large intracellular loop of the alpha1 subunit of the glycine receptor (GlyR) was used as "bait" to search a human brain library for proteins that may interact with this receptor. The GlyR is the major inhibitory ligand-gated ion channel in the spinal cord and lower brainstem, and is a member of the nicotinicoid superfamily of receptors. These in vitro studies identified the leptin receptor as a potential binding partner for GlyR, and this interaction was confirmed in binding studies that used the cytoplasmic loop of the GlyR as an affinity ligand for homogenized tissue from rat spinal cords and lower brainstem. Mass spectrometric analyses of eluants showed that the leptin receptor was specifically extracted from the homogenized and solubilized tissue. The long form of the leptin receptor is expressed in the hypothalamus (as is the GlyR) and among its other functions, it quickly evokes a satiation response upon binding leptin. Our in vitro results suggest that this rapid initial response may be mediated through direct interaction of the leptin receptor with GlyR or a related nicotinicoid family member homolog.