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Cell Chem Biol. 2019 Mar 21. pii: S2451-9456(19)30080-7. doi: 10.1016/j.chembiol.2019.03.003. [Epub ahead of print]

AKAP95 Organizes a Nuclear Microdomain to Control Local cAMP for Regulating Nuclear PKA.

Author information

1
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology, University of California, 9500 Gilman Drive, BRF-II 1120, La Jolla, CA 92093-0702, USA.
2
Department of Pharmacology, University of California, 9500 Gilman Drive, BRF-II 1120, La Jolla, CA 92093-0702, USA.
3
Department of Molecular Pharmacology, Institute of Cardiovascular and Medical Science, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
4
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology, University of California, 9500 Gilman Drive, BRF-II 1120, La Jolla, CA 92093-0702, USA. Electronic address: jzhang32@ucsd.edu.

Abstract

Contrary to the classic model of protein kinase A (PKA) residing outside of the nucleus, we identify a nuclear signaling complex that consists of AKAP95, PKA, and PDE4D5 and show that it forms a functional cyclic AMP (cAMP) signaling microdomain. Locally generated cAMP can accumulate within the vicinity of this complex; however, when cAMP is generated at the plasma membrane, PDE4 serves as a local sink and PDE3 as a barrier to prevent accumulation of cAMP within the microdomain as a means of controlling activation of tethered nuclear PKA.

KEYWORDS:

FRET biosensors; compartmentalization; imaging; spatiotemporal

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