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

Published

Journal Article

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, 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.

Full Text

Duke Authors

Cited Authors

  • Wooldridge, AA; Fortner, CN; Lontay, B; Akimoto, T; Neppl, RL; Facemire, C; Datto, MB; Kwon, A; McCook, E; Li, P; Wang, S; Thresher, RJ; Miller, SE; Perriard, J-C; Gavin, TP; Hickner, RC; Coffman, TM; Somlyo, AV; Yan, Z; Haystead, TAJ

Published Date

  • April 25, 2008

Published In

Volume / Issue

  • 283 / 17

Start / End Page

  • 11850 - 11859

PubMed ID

  • 18310078

Pubmed Central ID

  • 18310078

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M708628200

Language

  • eng

Conference Location

  • United States