Dataset Information

Receptor-independent modulation of cAMP-dependent protein kinase and protein phosphatase 2A signaling in cardiac myocytes by nitroxyl

ABSTRACT: Sympathetic activation is the main driver of cardiac inotropy and lusitropy. Stimulation of the -adrenoceptor (AR) signaling cascade leads to activation of cAMP-dependent protein kinase (PKA) and subsequent cardiac protein phosphorylation, which is counteracted by the corresponding protein phosphatases 2A (PP2A). Both, kinase and phosphatase are sensitive to oxidation. For PKA, the oxidant-mediated mode of regulation has been described to occur by interdisulfide formation between type I regulatory subunits (PKA-RI). Furthermore, oxidant-mediated intradisulfide formation in the catalytic subunit of PKA and PP2A was shown to inhibit kinase or phosphatase activity, respectively. Nitroxyl donors exert positive inotropic and lusitropic effects in cardiac myocytes.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Heart, Regular Ventricular Cardiac Myocyte

SUBMITTER: Christoph Krisp

LAB HEAD: Friederike Cuello

PROVIDER: PXD019808 | Pride | 2020-10-29

REPOSITORIES: Pride

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Receptor-independent modulation of cAMP-dependent protein kinase and protein phosphatase signaling in cardiac myocytes by oxidizing agents.

Diering Simon S Stathopoulou Konstantina K Goetz Mara M Rathjens Laura L Harder Sönke S Piasecki Angelika A Raabe Janice J Schulz Steven S Brandt Mona M Pflaumenbaum Julia J Fuchs Ulrike U Donzelli Sonia S Sadayappan Sakthivel S Nikolaev Viacheslav O VO Flenner Frederik F Ehler Elisabeth E Cuello Friederike F

The Journal of biological chemistry 20200831 45

The contraction and relaxation of the heart is controlled by stimulation of the β1-adrenoreceptor (AR) signaling cascade, which leads to activation of cAMP-dependent protein kinase (PKA) and subsequent cardiac protein phosphorylation. Phosphorylation is counteracted by the main cardiac protein phosphatases, PP2A and PP1. Both kinase and phosphatases are sensitive to intramolecular disulfide formation in their catalytic subunits that inhibits their activity. Additionally, intermolecular disulfide ...[more]

PMID: 32868295

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Project description:Musante2017 - Switching behaviour of PP2A inhibition by ARPP-16 - mutual inhibitions and PKA inhibits MAST3 This model is described in the article: Reciprocal regulation of ARPP-16 by PKA and MAST3 kinases provides a cAMP-regulated switch in protein phosphatase 2A inhibition. Musante V, Li L, Kanyo J, Lam TT, Colangelo CM, Cheng SK, Brody AH, Greengard P, Le Novère N, Nairn AC. Elife 2017 Jun; 6: Abstract: ARPP-16, ARPP-19, and ENSA are inhibitors of protein phosphatase PP2A. ARPP-19 and ENSA phosphorylated by Greatwall kinase inhibit PP2A during mitosis. ARPP-16 is expressed in striatal neurons where basal phosphorylation by MAST3 kinase inhibits PP2A and regulates key components of striatal signaling. The ARPP-16/19 proteins were discovered as substrates for PKA, but the function of PKA phosphorylation is unknown. We find that phosphorylation by PKA or MAST3 mutually suppresses the ability of the other kinase to act on ARPP-16. Phosphorylation by PKA also acts to prevent inhibition of PP2A by ARPP-16 phosphorylated by MAST3. Moreover, PKA phosphorylates MAST3 at multiple sites resulting in its inhibition. Mathematical modeling highlights the role of these three regulatory interactions to create a switch-like response to cAMP. Together, the results suggest a complex antagonistic interplay between the control of ARPP-16 by MAST3 and PKA that creates a mechanism whereby cAMP mediates PP2A disinhibition. This model is hosted on BioModels Database and identified by: BIOMD0000000644. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Musante2017 - Switching behaviour of PP2A inhibition by ARPP-16 - mutual inhibitions and PKA inhibits MAST3 and dominant negative effect This model is described in the article: Reciprocal regulation of ARPP-16 by PKA and MAST3 kinases provides a cAMP-regulated switch in protein phosphatase 2A inhibition. Musante V, Li L, Kanyo J, Lam TT, Colangelo CM, Cheng SK, Brody AH, Greengard P, Le Novère N, Nairn AC. Elife 2017 Jun; 6: Abstract: ARPP-16, ARPP-19, and ENSA are inhibitors of protein phosphatase PP2A. ARPP-19 and ENSA phosphorylated by Greatwall kinase inhibit PP2A during mitosis. ARPP-16 is expressed in striatal neurons where basal phosphorylation by MAST3 kinase inhibits PP2A and regulates key components of striatal signaling. The ARPP-16/19 proteins were discovered as substrates for PKA, but the function of PKA phosphorylation is unknown. We find that phosphorylation by PKA or MAST3 mutually suppresses the ability of the other kinase to act on ARPP-16. Phosphorylation by PKA also acts to prevent inhibition of PP2A by ARPP-16 phosphorylated by MAST3. Moreover, PKA phosphorylates MAST3 at multiple sites resulting in its inhibition. Mathematical modeling highlights the role of these three regulatory interactions to create a switch-like response to cAMP. Together, the results suggest a complex antagonistic interplay between the control of ARPP-16 by MAST3 and PKA that creates a mechanism whereby cAMP mediates PP2A disinhibition. This model is hosted on BioModels Database and identified by: BIOMD0000000645. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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			Action	DRS
	160615_uniprot-RAT.fasta	Fasta
	290419_sh_LR_1.raw	Raw
	290419_sh_LR_2.mzML	Mzml
	290419_sh_LR_2.mzid.gz	Mzid
	290419_sh_LR_2.pdResult	Other