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The primary cilium is a cell surface organelle that has been described as a signaling hub because it concentrates a large number of specialized signaling components within its tiny volume. In particular, primary cilia sequester diverse GPCRs connected to cAMP signaling, such as receptors for dopamine (D1R), serotonin (5-HT6) and somatostatin (SSTR3). Interest in ciliary cAMP signaling has expanded greatly following the discovery that cAMP-dependent protein kinase A (PKA) is among the kinases regulating the ciliary transcription factors that mediate canonical Hedgehog (Hh) signaling (i.e. through phosphorylation of Gli transcription factors). This presentation will describe optical approaches for interrogating the cAMP signaling microdomain of the primary cilium. Our direct organelle measurements challenge some of the assumptions about the nature of cAMP signaling in the ciliary space and suggest possible roles for GPCRs in Hh regulation.
