Role of KCTD proteins in striatal signaling

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Project Summary Alterations in striatal cAMP signal transduction contribute to the progression of movement disorders, whose increasing prevalence present a significant public health concern. Therapeutic options for movement disorders are limited in part by a deficient understanding of the molecular control of cAMP signaling in striatal neurons. Although tremendous progress has been made in unraveling the cAMP pathway, complexity of cAMP regulation in the striatum coupled with the large number of players with pivotal roles not yet fully elucidated has slowed progress towards more effective care strategies. To overcome this barrier, our long-term goal is to better understand the mechanisms and principles that control striatal cAMP signaling. The proposed work focuses on the role of Potassium Channel Tetramerization (KCTD) proteins in modulation of striatal signaling through G protein coupled receptors (GPCRs). KCTD proteins were recently implicated in GPCR signaling both directly by engaging with G proteins and indirectly by influencing zinc influx through zinc transporters. However, the details of KCTD regulation of G protein signaling and consequences of zinc on striatal signaling are only beginning to emerge. The goal of this proposal is elucidation of the KCTD-Zinc-cAMP signaling axis in the native neuronal environment. In Aim 1, we will use biochemical assays to study negative feedback pressure that dynamically adjusts KCTD expression in the striatum followed by optical assays to study how KCTD regulate interaction of G proteins with effectors. Aim 2 will utilize biochemical assays and optical sensors in live neurons to delineate precise mechanistic details of KCTD and zinc on striatal cAMP signaling. In Aim 3, we will address how KCTDs shape native physiological signal interrogation by optically stimulating neuromodulatory release with concurrent 2-photon imaging of signal integration across intact circuits in genetically defined striatal neurons expressing optical sensors. In total, the proposed research is expected to be significant in that it will provide essential mechanistic and physiological insight into the KCTD-Zinc-cAMP impact on signaling processes critical for motor physiology.