Deletion of the Protein Kinase A/Protein Kinase G Target SMTNL1 Promotes an Exercise-adapted Phenotype in Vascular Smooth Muscle
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Date
2008-04-25
Authors
Wooldridge, Anne A.
Fortner, Christopher N.
Lontay, Beata
Akimoto, Takayuki
Neppl, Ronald L.
Facemire, Carie
Datto, Michael B.
Kwon, Ashley
McCook, Everett
Li, Ping
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Journal ISSN
Volume Title
Publisher
East Carolina University
Abstract
In 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 2008
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Citation
Journal of Biological Chemistry; 283:17 p. 11850-11859