Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 24, Pages 12066-12071Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1819730116
Keywords
FRET biosensors; calcium; cyclic AMP; primary cilium
Categories
Funding
- NIH/National Institutes for Dental and Craniofacial Research [R21 DE025921]
- Department of Veterans Affairs [1IS1BX003538-01, 1IS1BX004786-01, I21 BX004093]
- Harvard Catalyst [NIH 1Ul1 TR00102-01]
- VA [1IS1BX004786-01, 1159214, 849839, 1IS1BX003538-01] Funding Source: Federal RePORTER
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The primary cilium permits compartmentalization of specific signaling pathways, including elements of the Hedgehog (Hh) pathway. Hh transcriptional activity is thought to be negatively regulated by constitutively high ciliary cAMP maintained by the G alpha(s)-coupled GPCR, GPR161. However, cilia also sequester many other G alpha(s)-coupled GPCRs with unknown potential to regulate Hh. Here we used biosensors optimized for ciliary cAMP and strategies to isolate signals in the cilium from the cell body and neighboring cells. We found that ciliary cAMP was not elevated relative to cellular cAMP, inconsistent with constitutive cAMP production. G alpha(s)-coupled GPCRs (e.g., the 5-HT6 serotonin and D1R dopamine receptor) had reduced ability to generate cAMP upon trafficking to the ciliary membrane. However, activation of the Hh pathway restored or amplified GPCR function to permit cAMP elevation selectively in the cilium. Hh therefore enables its own local GPCR-dependent cAMP regulatory circuit. Considering that GPCRs comprise much of the druggable genome, these data suggest alternative strategies to modify Hh signaling.
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