Deletion of the Protein Kinase A/Protein Kinase G Target SMTNL1 Promotes an Exercise-adapted Phenotype in Vascular Smooth Muscle

Wooldridge, Anne A.Fortner, Christopher N.Lontay, BeataAkimoto, TakayukiNeppl, Ronald L.Facemire, CarieDatto, Michael B.Kwon, AshleyMcCook, EverettLi, PingWang, ShiliangThresher, Randy J.Miller, Sara E.Perriard, Jean-ClaudeGavin, Timothy PatrickHickner, Robert C.Coffman, Thomas M.Somlyo, Avril V.Yan, ZhenHaystead, Timothy A. J.2011-04-282011-05-162011-04-282011-05-162008-04-25Journal of Biological Chemistry; 283:17 p. 11850-11859http://hdl.handle.net/10342/3427In vivo protein kinases A and G (PKA 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 PKG/PKA, 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, con- tractile 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. Originally published Journal of Biological Chemistry, Vol. 283, No. 17, Apr 2008en-USAuthor notified of opt-out rights by Cammie Jennings prior to upload of this article.Exercise adapted phenotypeProtein kinasesVascular smooth muscleDeletion of the Protein Kinase A/Protein Kinase G Target SMTNL1 Promotes an Exercise-adapted Phenotype in Vascular Smooth MuscleArticlePMC243107710.1074/jbc.M708628200