Interaction of Protein Kinase C and cAMP-dependent Pathways in the Phosphorylation of the Na,K-ATPase

Feschenko, Marina S.; Stevenson, Elizabeth; Sweadner, Kathleen J.

doi:10.1074/jbc.m005869200

Cited by 60 publications

(52 citation statements)

References 62 publications

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“…Unlike PP1, PP2A is not a classical target for cAMP action, although reports exist describing cAMP-dependent PP2A activation (75,76); however, the mechanistic details for cAMP stimulation of PP2A are still unknown. PP2A is a major serine/ threonine phosphatase involved in cell signaling.…”

Section: Discussionmentioning

confidence: 99%

A Novel Epac-Rap-PP2A Signaling Module Controls cAMP-dependent Akt Regulation

Hong

Lou²,

Gupta

et al. 2008

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

A Novel Epac-Rap-PP2A Signaling Module Controls cAMP-dependent Akt Regulation

Hong

Lou²,

Gupta

et al. 2008

Journal of Biological Chemistry

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“…A few other studies have suggested that PP2A can be activated by forskolin (14,32), a drug normally associated with activation of adenylyl cyclase and generation of cAMP. However, those studies suggested an indirect role for forskolin that did not depend on PKA, and perhaps did not depend on cAMP.…”

Section: Discussionmentioning

confidence: 99%

Protein kinase A activates protein phosphatase 2A by phosphorylation of the B56δ subunit

Ahn

McAvoy

Rakhilin

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

243

242

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Our previous studies of DARPP-32 in striatal slices have shown that activation of D1 receptors leads to cAMP-dependent dephosphorylation of Thr-75, the Cdk5 site in DARPP-32. In the current study, we have elucidated a mechanism whereby protein phosphatase 2A (PP2A) is activated by a cAMP/PKA-dependent pathway, leading to dephosphorylation of Thr-75. PP2A consists of a catalytic C subunit that associates with the scaffolding A subunit and a variety of B subunits. We have found that the A/C subunits of PP2A, in association with the B56␦ (or PPP2R5D) regulatory subunit, is an active DARPP-32 phosphatase. The B56␦ subunit expressed in HEK293 cells forms a heterotrimeric assembly that catalyzes PKA-mediated dephosphorylation at Thr-75 in DARPP-32 (also cotransfected into HEK293 cells). The B56␦ subunit is phosphorylated by PKA, and this increases the overall activity of PP2A in vitro and in vivo. Among four PKA-phosphorylation sites identified in B56␦ in vitro, Ser-566 was found to be critical for the regulation of PP2A activity. Moreover, Ser-566 was phosphorylated by PKA in response to activation of D1 receptors in striatal slices. Based on these studies, we propose that the B56␦/A/C PP2A complex regulates the dephosphorylation of DARPP-32 at Thr-75, thereby helping coordinate the efficacy of dopaminergic neurotransmission in striatal neurons. Moreover, stimulation of protein phosphatase activity by this mechanism may represent an important signaling pathway regulated by cAMP in neurons and other types of cell.cAMP ͉ DARPP-32 ͉ protein phosphorylation D ARPP-32 is a phosphoprotein that is highly enriched in dopaminoceptive medium-sized spiny neurons in the striatum and nucleus accumbens (1, 2). A variety of biochemical studies as well as targeted deletion and mutation of DARPP-32 in mice have shown that DARPP-32 plays a critical role in the actions of dopamine as well as in the actions of antipsychotic drugs, drugs of abuse, and other agents that modulate dopamine levels in the brain (2-5). Through activation of the D1 subclass of receptors, dopamine increases cAMP, activates protein kinase A (PKA), and phosphorylates Thr-34 of DARPP-32. Phosphorylation at Thr-34 converts DARPP-32 into a potent, high-affinity inhibitor of the broad specificity serine/threonine protein phosphatase, PP-1, leading to increased phosphorylation of many physiologically important substrates in medium spiny neurons, including neurotransmitter receptors, voltage-gated ion channels, ion pumps, protein kinases, and transcription factors (1, 2).In addition to Thr-34, DARPP-32 is phosphorylated at multiple sites by several protein kinases, including CK1, CK2 and Cdk5 (6-9). In particular, phosphorylation of Thr-75 by Cdk5 blocks PKA-mediated phosphorylation of Thr-34 of DARPP-32, thereby modulating the efficacy of the dopamine/D1/cAMP/ PKA/DARPP-32/PP1 signaling cascade (8). Our previous studies have found that there is a reciprocal relationship between the phosphorylation status of . Under basal conditions in striatal neurons in vivo or in vit...

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“…1A suggests that effects are not sustained long term. This may reflect a cellular homeostatic response to activation of cAMP-dependent signaling that terminates a phosphorylation-dependent part of the signal as discussed previously (37). For the variable we measure here, mechanisms that inactivate the downstream oxidative signaling pathway or directly activate deglutathionylation may have addi-FIGURE 5.…”

Section: Namentioning

confidence: 99%

Activation of cAMP-dependent Signaling Induces Oxidative Modification of the Cardiac Na+-K+ Pump and Inhibits Its Activity

White

Liu

García

et al. 2010

Journal of Biological Chemistry

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Cellular signaling can inhibit the membrane Na؉ -K ؉ pump via protein kinase C (PKC)-dependent activation of NADPH oxidase and a downstream oxidative modification, glutathionylation, of the ␤ 1 subunit of the pump ␣/␤ heterodimer. It is firmly established that cAMP-dependent signaling also regulates the pump, and we have now examined the hypothesis that such regulation can be mediated by glutathionylation. Exposure of rabbit cardiac myocytes to the adenylyl cyclase activator forskolin increased the co-immunoprecipitation of NADPH oxidase subunits p47 phox and p22 phox , required for its activation, and increased superoxide-sensitive fluorescence. Forskolin also increased glutathionylation of the Na ؉ -K ؉ pump ␤ 1 subunit and decreased its co-immunoprecipitation with the ␣ 1 subunit, findings similar to those already established for PKC-dependent signaling. The decrease in co-immunoprecipitation indicates a decrease in the ␣ 1 /␤ 1 subunit interaction known to be critical for pump function. In agreement with this, forskolin decreased ouabain-sensitive electrogenic Na ؉ -K ؉ pump current (arising from the 3:2 Na ؉ :K ؉ exchange ratio) of voltage-clamped, internally perfused myocytes. The decrease was abolished by the inclusion of superoxide dismutase, the inhibitory peptide for the ⑀-isoform of PKC or inhibitory peptide for NADPH oxidase in patch pipette solutions that perfuse the intracellular compartment. Pump inhibition was also abolished by inhibitors of protein kinase A and phospholipase C. We conclude that cAMPand PKC-dependent inhibition of the cardiac Na ؉ -K ؉ pump occurs via a shared downstream oxidative signaling pathway involving NADPH oxidase activation and glutathionylation of the pump ␤ 1 subunit.

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Interaction of Protein Kinase C and cAMP-dependent Pathways in the Phosphorylation of the Na,K-ATPase

Cited by 60 publications

References 62 publications

A Novel Epac-Rap-PP2A Signaling Module Controls cAMP-dependent Akt Regulation

A Novel Epac-Rap-PP2A Signaling Module Controls cAMP-dependent Akt Regulation

Protein kinase A activates protein phosphatase 2A by phosphorylation of the B56δ subunit

Activation of cAMP-dependent Signaling Induces Oxidative Modification of the Cardiac Na+-K+ Pump and Inhibits Its Activity

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