- Authors:
-
-
Lundby, Alicia
;
Close
0000-0002-1612-6041
Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Københavns Universitet - Andersen, Martin N ;
- Steffensen, Annette B ;
- Horn, Heiko ;
-
Kelstrup, Christian D
;
Close0000-0003-4647-1425
Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Københavns Universitet - Francavilla, Chiara ;
-
Jensen, Lars J
;
Close0000-0001-7885-715X
Disease Systems Biology Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Københavns Universitet -
Schmitt, Nicole
;
Close0000-0001-9482-9749
Danish Arrhythmia Research Centre, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, Københavns Universitet -
Thomsen, Morten B
;
Close0000-0002-2469-6458
Heart and Circulatory Research, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, Københavns Universitet -
Olsen, Jesper V
Close0000-0002-4747-4938
Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Københavns Universitet
-
Lundby, Alicia
;
- DOI:
- 10.1126/scisignal.2003506
- Abstract:
- β-Blockers are widely used to prevent cardiac arrhythmias and to treat hypertension by inhibiting β-adrenergic receptors (βARs) and thus decreasing contractility and heart rate. βARs initiate phosphorylation-dependent signaling cascades, but only a small number of the target proteins are known. We used quantitative in vivo phosphoproteomics to identify 670 site-specific phosphorylation changes in murine hearts in response to acute treatment with specific βAR agonists. The residues adjacent to the regulated phosphorylation sites exhibited a sequence-specific preference (R-X-X-pS/T), and integrative analysis of sequence motifs and interaction networks suggested that the kinases AMPK (adenosine 5'-monophosphate-activated protein kinase), Akt, and mTOR (mammalian target of rapamycin) mediate βAR signaling, in addition to the well-established pathways mediated by PKA (cyclic adenosine monophosphate-dependent protein kinase) and CaMKII (calcium/calmodulin-dependent protein kinase type II). We found specific regulation of phosphorylation sites on six ion channels and transporters that mediate increased ion fluxes at higher heart rates, and we showed that phosphorylation of one of these, Ser(92) of the potassium channel KV7.1, increased current amplitude. Our data set represents a quantitative analysis of phosphorylated proteins regulated in vivo upon stimulation of seven-transmembrane receptors, and our findings reveal previously unknown phosphorylation sites that regulate myocardial contractility, suggesting new potential targets for the treatment of heart disease and hypertension.
- Type:
- Journal article
- Language:
- English
- Published in:
- Science Signaling, 2013, Vol 6, Issue 278
- Main Research Area:
- Medical science
- Publication Status:
- Published
- Review type:
- Peer Review
- Submission year:
- 2013
- Scientific Level:
- Scientific
- ID:
- 242119723
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