Skip to main page content
U.S. flag

An official website of the United States government

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Jan;1866(1):64-73.
doi: 10.1016/j.bbamcr.2018.09.006. Epub 2018 Sep 18.

cAMP regulation of protein phosphatases PP1 and PP2A in brain

Shannon N Leslie  1 , Angus C Nairn  2
Affiliations
Review

cAMP regulation of protein phosphatases PP1 and PP2A in brain

Shannon N Leslie et al. Biochim Biophys Acta Mol Cell Res. 2019 Jan.

Abstract

Normal functioning of the brain is dependent upon a complex web of communication between numerous cell types. Within neuronal networks, the faithful transmission of information between neurons relies on an equally complex organization of inter- and intra-cellular signaling systems that act to modulate protein activity. In particular, post-translational modifications (PTMs) are responsible for regulating protein activity in response to neurochemical signaling. The key second messenger, cyclic adenosine 3',5'-monophosphate (cAMP), regulates one of the most ubiquitous and influential PTMs, phosphorylation. While cAMP is canonically viewed as regulating the addition of phosphate groups through its activation of cAMP-dependent protein kinases, it plays an equally critical role in regulating removal of phosphate through indirect control of protein phosphatase activity. This dichotomy of regulation by cAMP places it as one of the key regulators of protein activity in response to neuronal signal transduction throughout the brain. In this review we focus on the role of cAMP in regulation of the serine/threonine phosphatases protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) and the relevance of control of PP1 and PP2A to regulation of brain function and behavior.

Keywords: Brain; PKA; PP1; PP2A; Striatum; cAMP.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.. cAMP-mediated inhibition of PP1
A schematic of cAMP-mediated inhibition of PP1 via activation of DARPP-32. An elevation in cAMP, which can result from a variety of stimuli, leads to activation of PKA. Subsequently, PKA phosphorylates DARPP-32 at Thr-34 converting the protein into a potent inhibitor of PP1. As a result, suppression of PP1 activity contributes to increased phosphorylation of substrates for a variety of kinases, including PKA. This can lead to “cross-talk” between PKA signaling pathways and other kinase pathways or to “amplification” of PKA signaling by preventing dephosphorylation of substrates for PKA.
Figure 2.
Figure 2.. PKA enhancement of DARPP-32-mediated PP1 inhibition
cAMP activates PKA which phosphorylates DARPP-32 at Thr-34 resulting in DARPP-32-mediated inhibition of PP1. However, DARPP-32 is also phosphorylated by the kinase Cdk5 at Thr-75. When DARPP-32 is phosphorylated at Thr-75 it suppresses PKA activity. Additionally, the p-Thr-75 form of DARPP-32 antagonizes Thr-34 phosphorylation by PKA, diminishing the ability of DARPP-32 to inhibit PP1. PKA also phosphorylates and activates a specific heterotrimeric form of PP2A that selectively dephosphorylates DARPP-32 at Thr-75. Thus, PKA drives the phosphorylation of DARPP-32 as well as driving dephosphorylation of an antagonistic phosphorylation site thus enhancing PKA mediated inhibition of PP1 via DARPP-32.
Figure 3.
Figure 3.. cAMP mediated activation of PP2A
cAMP activates PKA which phosphorylates the B56δ subunit of the PP2A heterotrimer. This phosphorylation increases the phosphatase activity of the enzyme resulting in greater dephosphorylation of selected PP2A substrates.
Figure 4.
Figure 4.. Disinhibition of PP2A by cAMP
Schematic of cAMP-mediated disinhibition of PP2A via PKA and ARPP-16. Without PKA phosphorylation, MAST3 kinase phosphorylates ARPP-16 at Ser-46. This form of ARPP-16 selectively inhibits the activity of specific heterotrimeric forms of PP2A. cAMP activates PKA which phosphorylates ARPP-16 at Ser-88, which interacts with PP2A to make the enzyme non-inhibitable. Phosphorylation of the Ser-88 and Ser-46 sites is mutually antagonistic, thus phosphorylation at Ser-88 opposes phosphorylation at Ser-46 and vice versa. PKA is also able to phosphorylate and inhibit MAST3 kinase further reducing Ser-46 phosphorylation.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Nestler EJ, Greengard P, Protein phosphorylation in the brain, Nature. 305 (1983) 583–588. doi:10.1038/305583a0. - DOI - PubMed
    1. Walaas SI, Greengard P, Protein phosphorylation and neuronal function., Pharmacol. Rev 43 (1991) 299–349. - PubMed
    1. Sutherland EW, Rall TW, Fractionation and characterization of a cyclic adenine ribonucleotide formed by tissue particles, J. Biol. Chem 232 (1958) 1077–1091. - PubMed
    1. Cooper DMF, Mons N, Karpen JW, Adenylyl cyclases and the interaction between calcium and cAMP signalling, Nature. 374 (1995) 421–424. doi:10.1038/374421a0. - DOI - PubMed
    1. Beaulieu J-M, Espinoza S, Gainetdinov RR, Dopamine receptors - IUPHAR Review 13, Br. J. Pharmacol 172 (2015) 1–23. doi:10.1111/bph.12906. - DOI - PMC - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources