| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Division of Reproductive Biology, Department of Obstetrics and Gynecology, and
* Immunology and Allergy, Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA
1Correspondence: Division of Reproductive Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, 300 Pasteur Dr., Room A344, Stanford, CA 94305-5317, USA. E-mail: marco.conti{at}stanford.edu
The airways of mice deficient in the cAMP phosphodiesterase PDE4D gene are refractory to muscarinic cholinergic stimulation. This study was undertaken to determine whether altered smooth muscle contractility causes the PDE4D-/- phenotype. A major disruption in contractility was observed in isolated PDE4D-/- tracheas, with a 60% reduction in maximal tension and a fivefold decrease in sensitivity to muscarinic cholinergic agonists. Conversely, responses to KCl or arginine vasopressin were unaffected. PDE4D is the predominant PDE4 form in tracheal extracts and PDE4D mRNA is expressed in smooth muscle where muscarinic binding sites are most abundant. Cyclic AMP accumulation in response to acute Gs
-coupled receptor stimulation was increased up to fourfold in the airway of PDE4D-/- mice when compared with wild-type. This increase in cAMP was associated with an increased sensitivity to PGE2-induced relaxation of the PDE4D-/-tracheas. Furthermore, a blockade of prostanoid accumulation in PDE4D-/- tracheas restored the response to muscarinic cholinergic stimulation in vitro and in vivo. These results demonstrate that PDE4D plays a key role in balancing relaxant and contracting cues in airway smooth muscle, suggesting that natural mutations in the PDE4D gene have profound effects on airway tone.—Méhats, C., Jin, S.-L. C., Wahlstrom, J., Law, E., Umetsu, D., Conti, M. PDE4D plays a critical role in the control of airway smooth muscle contraction.
Key Words: cyclic AMP • metabolism • second messengers • trachea
This article has been cited by other articles:
|
|
 |
|
  M. D. Bruss, W. Richter, K. Horner, S.-L. C. Jin, and M. Conti Critical Role of PDE4D in {beta}2-Adrenoceptor-dependent cAMP Signaling in Mouse Embryonic Fibroblasts J. Biol. Chem., August 15, 2008; 283(33): 22430 - 22442. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Baroffio, E. Crimi, and V. Brusasco Review: Airway smooth muscle as a model for new investigative drugs in asthma Therapeutic Advances in Respiratory Disease, June 1, 2008; 2(3): 129 - 139. [Abstract] [PDF]
|
|
|
|
 |
|
 A. Hu, G. Nino, J. S. Grunstein, S. Fatma, and M. M. Grunstein Prolonged heterologous {beta}2-adrenoceptor desensitization promotes proasthmatic airway smooth muscle function via PKA/ERK1/2-mediated phosphodiesterase-4 induction Am J Physiol Lung Cell Mol Physiol, June 1, 2008; 294(6): L1055 - L1067. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. K. Billington, I. R. Le Jeune, K. W. Young, and I. P. Hall A Major Functional Role for Phosphodiesterase 4D5 in Human Airway Smooth Muscle Cells Am. J. Respir. Cell Mol. Biol., January 1, 2008; 38(1): 1 - 7. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Peter, S. L. C. Jin, M. Conti, A. Hatzelmann, and C. Zitt Differential Expression and Function of Phosphodiesterase 4 (PDE4) Subtypes in Human Primary CD4+ T Cells: Predominant Role of PDE4D J. Immunol., April 15, 2007; 178(8): 4820 - 4831. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Houslay, G. S. Baillie, and D. H. Maurice cAMP-Specific Phosphodiesterase-4 Enzymes in the Cardiovascular System: A Molecular Toolbox for Generating Compartmentalized cAMP Signaling Circ. Res., April 13, 2007; 100(7): 950 - 966. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Omori and J. Kotera Overview of PDEs and Their Regulation Circ. Res., February 16, 2007; 100(3): 309 - 327. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Cheng and J. P. Grande Cyclic Nucleotide Phosphodiesterase (PDE) Inhibitors: Novel Therapeutic Agents for Progressive Renal Disease Experimental Biology and Medicine, January 1, 2007; 232(1): 38 - 51. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. T. Bender and J. A. Beavo Cyclic Nucleotide Phosphodiesterases: Molecular Regulation to Clinical Use Pharmacol. Rev., September 1, 2006; 58(3): 488 - 520. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Cheng, M. M. D. Encarnacion, G. M. Warner, C. E. Gray, K. A. Nath, and J. P. Grande TGF-{beta}1 stimulates monocyte chemoattractant protein-1 expression in mesangial cells through a phosphodiesterase isoenzyme 4-dependent process Am J Physiol Cell Physiol, October 1, 2005; 289(4): C959 - C970. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Lynch, G. S. Baillie, A. Mohamed, X. Li, C. Maisonneuve, E. Klussmann, G. van Heeke, and M. D. Houslay RNA Silencing Identifies PDE4D5 as the Functionally Relevant cAMP Phosphodiesterase Interacting with {beta}Arrestin to Control the Protein Kinase A/AKAP79-mediated Switching of the {beta}2-Adrenergic Receptor to Activation of ERK in HEK293B2 Cells J. Biol. Chem., September 30, 2005; 280(39): 33178 - 33189. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Liu, A. Veilleux, L. Zhang, A. Young, E. Kwok, F. Laliberte, C. Chung, M. R. Tota, D. Dube, R. W. Friesen, et al. Dynamic Activation of Cystic Fibrosis Transmembrane Conductance Regulator by Type 3 and Type 4D Phosphodiesterase Inhibitors J. Pharmacol. Exp. Ther., August 1, 2005; 314(2): 846 - 854. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Barnes and R. A. Stockley COPD: current therapeutic interventions and future approaches Eur. Respir. J., June 1, 2005; 25(6): 1084 - 1106. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Wallace, L. A. Johnston, E. Huston, D. MacMaster, T. M. Houslay, Y.-F. Cheung, L. Campbell, J. E. Millen, R. A. Smith, I. Gall, et al. Identification and Characterization of PDE4A11, a Novel, Widely Expressed Long Isoform Encoded by the Human PDE4A cAMP Phosphodiesterase Gene Mol. Pharmacol., June 1, 2005; 67(6): 1920 - 1934. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-F. Tang, Y.-H. Song, J.-C. Chen, J.-Q. Chen, and P. Wang Upregulation of Phosphodiesterase-4 in the Lung of Allergic Rats Am. J. Respir. Crit. Care Med., April 15, 2005; 171(8): 823 - 828. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. Barnes, G. Livera, P. Huang, C. Sun, W. K. O'Neal, M. Conti, M. J. Stutts, and S. L. Milgram Phosphodiesterase 4D Forms a cAMP Diffusion Barrier at the Apical Membrane of the Airway Epithelium J. Biol. Chem., March 4, 2005; 280(9): 7997 - 8003. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Cheng, M. A. Thompson, H. J. Walker, C. E. Gray, M. M. Diaz Encarnacion, G. M. Warner, and J. P. Grande Differential regulation of mesangial cell mitogenesis by cAMP phosphodiesterase isozymes 3 and 4 Am J Physiol Renal Physiol, November 1, 2004; 287(5): F940 - F953. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
