HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 17, 11850-11859, April 25, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/17/11850    most recent M708628200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wooldridge, A. A. Articles by Haystead, T. A. J. Search for Related Content PubMed PubMed Citation Articles by Wooldridge, A. A. Articles by Haystead, T. A. J. Social Bookmarking                      What's this?

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

Anne A. Wooldridge, 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, and Timothy A. J. Haystead¹

From the Departments of Pharmacology, Medicine, and ^||Pathology, Duke University, Medical Center, Durham, North Carolina 27710, the ^¶Department of Molecular Physiology, University of Virginia, Charlottesville, Virginia 22908, the ^**Animal Models Core Facility, University of North Carolina, Chapel Hill, North Carolina 27599, the Institute of Cell Biology, ETH-Zurich CH-8093, Switzerland, and the Department of Exercise and Sport Science, East Carolina University, Greenville, North Carolina 27878

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 -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.

Received for publication, October 17, 2007 , and in revised form, February 20, 2008.

^* This work was supported by National Institutes of Health Grants DK065954-02 and 5 R01 HL078795-04. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S8 and Table S1.

¹ To whom correspondence should be addressed: Duke University Medical Center Box 3813, C119 LSRC Research Drive, Durham, NC 27710. Tel.: 919-613-8606; Fax: 919-668-0977; E-mail: hayst001{at}mc.duke.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				R. L. Neppl, L. T. Lubomirov, K. Momotani, G. Pfitzer, M. Eto, and A. V. Somlyo Thromboxane A2-induced Bi-directional Regulation of Cerebral Arterial Tone J. Biol. Chem., March 6, 2009; 284(10): 6348 - 6360. [Abstract] [Full Text] [PDF]