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Updated: Aug 13, 2025
08:49
Mapping the Cellular Distribution of an Optogenetic Protein Using a Light-Stimulation Grid
Published on: January 26, 2024
282
Soluble cyclase-mediated nuclear cAMP synthesis is sufficient for cell proliferation
Alejandro Pizzoni1, Xuefeng Zhang1, Nyla Naim1
1Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.
Summary
A novel three-wave model reveals that nuclear cAMP generation by soluble adenylyl cyclase (sAC) is essential for thyroid cell proliferation, acting downstream of plasma membrane and endosomal signaling.
Area of Science:
- Cell Biology
- Molecular Endocrinology
- Signal Transduction
Background:
- Cyclic adenosine monophosphate (cAMP) traditionally originates from the plasma membrane.
- Internalized G protein-coupled receptors (GsPCRs) can sustain signaling from endosomes and the trans-Golgi network (TGN), creating a second cAMP wave linked to nuclear events.
Purpose of the Study:
- To investigate the role of nuclear cAMP generation in thyroid cell proliferation.
- To elucidate the mechanism of TSHR-mediated signaling and its impact on nuclear events.
Main Methods:
- Utilized pharmacological and genetic inhibition of soluble adenylyl cyclase (sAC).
- Employed nuclear-targeted optogenetic actuators for light-stimulated cAMP synthesis.
- Assessed PKA activation, CREB phosphorylation, and cell proliferation.
Main Results:
- TSHR internalization triggers calcium-mediated nuclear sAC activation, leading to PKA activation and CREB phosphorylation.
- Inhibition of sAC blunted nuclear cAMP accumulation and cell proliferation, without affecting cytosolic cAMP.
- Increased nuclear sAC expression enhanced cell proliferation, and optogenetic nuclear cAMP synthesis mimicked TSH's proliferative effects.
Conclusions:
- Propose a three-wave cAMP model where nuclear sAC generates a "third wave" essential for thyroid cell proliferation.
- Nuclear cAMP generation by sAC is sufficient and rate-limiting for thyroid cell proliferation, downstream of PM and endosomal/TGN signaling.
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