Project summary G protein-coupled receptor kinases (GRKs) play a pivotal role in modulating neuromodulatory signals by altering GPCRs, with implications for a range of neurological and psychiatric conditions that affect sensation, mood, and movement. The inherent complexity of the GRK protein family, characterized by several similar paralogs and the broad regulation of numerous GPCRs, presents a significant challenge in delineating their functions in vivo. Our research in the nematode Caenorhabditis elegans which has only two GRK paralogs (GRK-1 and GRK-2) has brought to light novel mechanisms of GRK function and specificity. In particular, our studies have found that mutants of grk-2 exhibit impaired exploration behavior. We also found that loss of either the SSU-1 sulfotransferase or the FLP-1 neuropeptide partially mitigates these impairments, and the concurrent loss of both SSU-1 and FLP-1 fully restores normal exploration behavior in grk-2 mutants, revealing an unexpected level of functional specificity in GRK-mediated signaling in vivo. Based on these insights, our proposed research has three main objectives. First, we will determine how GRK-2 interacts with the SSU-1 sulfotransferase pathway in sensory neurons to regulate exploratory locomotion. Second, we will decode the network mechanisms through which GRK-2 signaling in sensory neurons can regulate FLP-1 neuropeptide secretion from AVK interneurons, despite lacking direct synaptic connections. Third, we will elucidate the cooperative and independent roles of the distinct GRK paralogs GRK-1 and GRK-2 in modulating neuronal communication and behavior by studying their structural features, expression patterns, and behavioral impacts. Our comprehensive studies aim to unravel the intricate mechanisms of GRK regulation in regulating neuronal function and behavior.