2. Academic Validation
  3. Compartmentalized cAMP Generation by Engineered Photoactivated Adenylyl Cyclases

Compartmentalized cAMP Generation by Engineered Photoactivated Adenylyl Cyclases

  • Cell Chem Biol. 2019 Oct 17;26(10):1393-1406.e7. doi: 10.1016/j.chembiol.2019.07.004.
Colin P O'Banion 1,  Brianna M Vickerman 2,  Lauren Haar 1,  David S Lawrence 3
Affiliations

Affiliations

  • 1 Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
  • 2 Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, USA.
  • 3 Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: lawrencd@email.unc.edu.
PMID: 31353320 DOI: 10.1016/j.chembiol.2019.07.004
Abstract

Because small-molecule activators of adenylyl cyclases (AC) affect ACs cell-wide, it is challenging to explore the signaling consequences of AC activity emanating from specific intracellular compartments. We explored this issue using a series of engineered, optogenetic, spatially restricted, photoactivable adenylyl cyclases (PACs) positioned at the plasma membrane (PM), the outer mitochondrial membrane (OMM), and the nucleus (Nu). The biochemical consequences of brief photostimulation of PAC is primarily limited to the intracellular site occupied by the PAC. By contrast, sustained photostimulation results in distal cAMP signaling. Prolonged cAMP generation at the OMM profoundly stimulates nuclear protein kinase (PKA) activity. We have found that phosphodiesterases 3 (OMM and PM) and 4 (PM) modulate proximal (local) cAMP-triggered activity, whereas phosphodiesterase 4 regulates distal cAMP activity as well as the migration of PKA's catalytic subunit into the nucleus.

Keywords

optogenetics; phosphodiesterases; protein kinases; second messengers; signaling.

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