title: Deletion of the protein kinase A/protein kinase G target SMTNL1 promotes an exercise-adapted phenotype in vascular smooth muscle.
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, 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.
authors.affiliation: Department of Pharmacology, Medicine, Duke University, Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Anne A
authors.initials: AA
authors.lastname: Wooldridge
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Fortner
authors.forename: Beata
authors.initials: B
authors.lastname: Lontay
authors.forename: Takayuki
authors.initials: T
authors.lastname: Akimoto
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Neppl
authors.forename: Carie
authors.initials: C
authors.lastname: Facemire
authors.forename: Michael B
authors.initials: MB
authors.lastname: Datto
authors.forename: Ashley
authors.initials: A
authors.lastname: Kwon
authors.forename: Everett
authors.initials: E
authors.lastname: McCook
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Shiliang
authors.initials: S
authors.lastname: Wang
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Thresher
authors.forename: Sara E
authors.initials: SE
authors.lastname: Miller
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Perriard
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Gavin
authors.forename: Robert C
authors.initials: RC
authors.lastname: Hickner
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Coffman
authors.forename: Avril V
authors.initials: AV
authors.lastname: Somlyo
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
authors.forename: Timothy A J
authors.initials: TA
authors.lastname: Haystead
mesh_terms: D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D008954:Models, Biological; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009218:Myosins / Q000378:metabolism; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics* / Q000502:physiology; D010766:Phosphorylation; D010805:Physical Conditioning, Animal; D000096985:Calponins
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D009124:Muscle Proteins; D009218:Myosins; D010750:Phosphoproteins; C491838:SMTNL1 protein, mouse; D000096985:Calponins