Proteomic and Transcriptional Analysis of Cilia-Dependent Dopamine Receptor 1 Signaling

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ABSTRACT Modulation of dopaminergic signaling has therapeutic potential for numerous neurological conditions, including movement disorders, drug addiction, and anxiety disorders. One promising approach for modulation of dopaminergic pathways involves targeting specific dopamine receptors to differentially regulate individual signaling pathways. Yet, significant gaps in our understanding of dopamine receptor signaling remain and hinder such efforts. We have discovered that dopamine receptor 1 (D1) dynamically localizes to primary cilia on neurons in several brain regions, including the striatum. Primary cilia are cellular appendages that provide critical sensory and signaling functions. Numerous human diseases are now known to be caused by defects in primary cilia. Remarkably, we still know very little about how primary cilia impact neuronal function, despite the fact that most, if not all, central neurons in the mammalian brain possess a primary cilium. Primary cilia are restricted compartments and select G protein-coupled receptors (GPCRs), such as D1, are targeted to the ciliary membrane in neurons. Downstream effectors of GPCR signaling also localize to neuronal cilia, suggesting that primary cilia support specialized non-synaptic dopaminergic signaling. Indeed, we have discovered that disrupting cilia in D1-expressing neurons results in deficient D1 signaling, as well as reduced basal locomotor activity and obesity. In this proposal we will use cutting-edge approaches to identify the molecular mechanisms underlying the role of cilia in D1-expressing neurons and provide critical insight into the importance of cilia in D1 signaling. The outcomes of this work will fundamentally advance our understanding of D1 signaling in the striatum and may implicate cilia-specific factors as novel targets for therapeutics.