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Deletion of the protein kinase A/protein kinase G target SMTNL1 promotes an exercise-adapted phenotype in vascular smooth muscle.

J Biol Chem. 2008 Apr 25;283(17):11850-9. Epub 2008 Feb 29
Anne A Wooldridge 1 , Christopher N Fortner , Beata Lontay , Takayuki Akimoto , Ronald L Neppl , Carie Facemire , Michael B Datto , Ashley Kwon , Everett McCook , Ping Li , Shiliang Wang , Randy J Thresher , Sara E Miller , Jean-Claude Perriard , Timothy P Gavin , Robert C Hickner , Thomas M Coffman , Avril V Somlyo , Zhen Yan , Timothy A J Haystead
Anne A Wooldridge 1 , Christopher N Fortner , Beata Lontay , Takayuki Akimoto , Ronald L Neppl , Carie Facemire , Michael B Datto , Ashley Kwon , Everett McCook , Ping Li , Shiliang Wang , Randy J Thresher , Sara E Miller , Jean-Claude Perriard , Timothy P Gavin , Robert C Hickner , Thomas M Coffman , Avril V Somlyo , Zhen Yan , Timothy A J Haystead
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Author information
  • 1 Department of Pharmacology, Medicine, Duke University, Medical Center, Durham, North Carolina 27710, USA.

摘要


In vivo protein kinases A and G and PKG) coordinately phosphorylate a broad range of substrates to mediate their various physiological effects. The functions of many of these substrates have yet to be defined genetically. Herein we show a role for smoothelin-like protein 1 (SMTNL1), a novel in vivo target of in mediating vascular adaptations to exercise. Aortas from smtnl1(-/-) mice exhibited strikingly enhanced vasorelaxation before exercise, similar in extent to that achieved after endurance training of wild-type littermates. Additionally, contractile responses to alpha-adrenergic agonists were greatly attenuated. Immunological studies showed SMTNL1 is expressed in smooth muscle and type 2a striated muscle fibers. Consistent with a role in adaptations to exercise, smtnl1(-/-) mice also exhibited increased type 2a fibers before training and better performance after forced endurance training compared smtnl1(+/+) mice. Furthermore, exercise was found to reduce expression of SMTNL1, particularly in female mice. In both muscle types, SMTNL1 is phosphorylated at Ser-301 in response to adrenergic signals. In vitro SMTNL1 suppresses myosin phosphatase activity through a substrate-directed effect, which is relieved by Ser-301 phosphorylation. Our findings suggest roles for SMTNL1 in cGMP/cAMP-mediated adaptations to exercise through mechanisms involving direct modulation of contractile activity.