help button home button
AJRCMB
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Penn, R. B.
Right arrow Articles by Benovic, J. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Penn, R. B.
Right arrow Articles by Benovic, J. L.

Am. J. Respir. Cell Mol. Biol., Volume 19, Number 2, August, 1998 338-348

Mechanisms of Acute Desensitization of the beta 2AR-Adenylyl Cyclase Pathway in Human Airway Smooth Muscle

Raymond B. Penn, Reynold A. Panettieri Jr., and Jeffrey L. Benovic

Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University; and Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

beta 2-Adrenergic receptors (beta 2ARs) are important regulators of airway smooth muscle tone, and beta -sympathomimetic drugs are the most widely used agents in asthma therapy and are universally recognized as the treatment of choice for acute asthma attacks. Despite the clinical importance of beta -agonists and a good understanding of their mechanism of action in airway smooth muscle relaxation, surprisingly little is known about the manner in which the beta 2AR signaling pathway is regulated in human airway smooth muscle (HASM). In this communication, we characterize mechanisms underlying rapid desensitization of the HASM beta 2AR-adenylyl cyclase (AC) pathway. Acute homologous desensitization of beta 2AR-mediated cyclic adenosine monophosphate (cAMP) production was characterized by an ~ 60% loss of maximal responsiveness to isoproterenol (ISO) when cells were pretreated for 30 min with 1 µM ISO. Acute heterologous beta 2AR desensitization was characterized by an ~ 20% and 30% loss of maximal responsiveness to ISO challenge when cells were pretreated with forskolin and prostaglandin E2 (PGE2), respectively. Each form of desensitization was also characterized by an increase in the EC50 for ISO. beta 2AR sequestration was associated with but not required for homologous desensitization. However, sequestration was required for rapid resensitization. Minimal alterations in inherent AC activity were observed with both modes of desensitization, suggesting that the beta 2AR is the principal locus of regulation. Protein kinase inhibition by staurosporine largely reversed heterologous beta 2AR desensitization and had a small but significant effect on homologous desensitization. In contrast, bisindolylmaleimide IX, a specific PKC-inhibitor, had no effect on heterologous or homologous beta 2AR desensitization, suggesting that staurosporine effects were mediated by PKA inhibition. Overexpression of the G protein-coupled receptor kinase GRK2 in HASM cultures enhanced homologous desensitization. These data suggest that HASM beta 2ARs are highly susceptible to rapid desensitization by multiple agents, and identify both GRKs and PKA as important mediators of acute beta 2AR desensitization.




This article has been cited by other articles:


Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
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]

Home page
 J. Biol. Chem.Home page
Y. Wang, V. De Arcangelis, X. Gao, B. Ramani, Y.-s. Jung, and Y. Xiang
Norepinephrine- and Epinephrine-induced Distinct 2-Adrenoceptor Signaling Is Dictated by GRK2 Phosphorylation in Cardiomyocytes
J. Biol. Chem., January 25, 2008; 283(4): 1799 - 1807.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
D. Willoughby, G. S. Baillie, M. J. Lynch, A. Ciruela, M. D. Houslay, and D. M. F. Cooper
Dynamic Regulation, Desensitization, and Cross-talk in Discrete Subcellular Microdomains during beta2-Adrenoceptor and Prostanoid Receptor cAMP Signaling
J. Biol. Chem., November 23, 2007; 282(47): 34235 - 34249.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
X. Chen, J.-C. Dai, and E. M. Greenfield
Termination of immediate-early gene expression after stimulation by parathyroid hormone or isoproterenol
Am J Physiol Cell Physiol, November 1, 2002; 283(5): C1432 - C1440.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
R. M. Pascual, C. K. Billington, I. P. Hall, R. A. Panettieri Jr., J. E. Fish, S. P. Peters, and R. B. Penn
Mechanisms of cytokine effects on G protein-coupled receptor-mediated signaling in airway smooth muscle
Am J Physiol Lung Cell Mol Physiol, December 1, 2001; 281(6): L1425 - L1435.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
J. C. KIPS and R. A. PAUWELS
Long-acting Inhaled beta 2-Agonist Therapy in Asthma
Am. J. Respir. Crit. Care Med., September 15, 2001; 164(6): 923 - 932.
[Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
T. A. Wyatt and J. H. Sisson
Chronic ethanol downregulates PKA activation and ciliary beating in bovine bronchial epithelial cells
Am J Physiol Lung Cell Mol Physiol, September 1, 2001; 281(3): L575 - L581.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
C. K. Billington, R. M. Pascual, M. L. Hawkins, R. B. Penn, and I. P. Hall
Interleukin-1{beta} and Rhinovirus Sensitize Adenylyl Cyclase in Human Airway Smooth-Muscle Cells
Am. J. Respir. Cell Mol. Biol., May 1, 2001; 24(5): 633 - 639.
[Abstract] [Full Text]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
V. P. Krymskaya, A. J. Ammit, R. K. Hoffman, A. J. Eszterhas, and R. A. Panettieri Jr.
Activation of class IA PI3K stimulates DNA synthesis in human airway smooth muscle cells
Am J Physiol Lung Cell Mol Physiol, May 1, 2001; 280(5): L1009 - L1018.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
S. J. Mundell, M. E. Olah, R. A. Panettieri Jr., J. L. Benovic, and R. B. Penn
Regulation of G Protein-Coupled Receptor-Adenylyl Cyclase Responsiveness in Human Airway Smooth Muscle by Exogenous and Autocrine Adenosine
Am. J. Respir. Cell Mol. Biol., February 1, 2001; 24(2): 155 - 163.
[Abstract] [Full Text]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
A. J. Ammit, R. K. Hoffman, Y. Amrani, A. L. Lazaar, D. W. P. Hay, T. J. Torphy, R. B. Penn, and R. A. Panettieri Jr.
Tumor Necrosis Factor-alpha -Induced Secretion of RANTES and Interleukin-6 from Human Airway Smooth-Muscle Cells . Modulation by Cyclic Adenosine Monophosphate
Am. J. Respir. Cell Mol. Biol., December 1, 2000; 23(6): 794 - 802.
[Abstract] [Full Text]

Home page
 Am. J. Respir. Crit. Care Med.Home page
P. E. MOORE, J. D. LAPORTE, J. H. ABRAHAM, I. N. SCHWARTZMAN, C. N. YANDAVA, E. S. SILVERMAN, J. M. DRAZEN, M. P. WAND, R. A. PANETTIERI Jr., and S. A. SHORE
Polymorphism of the {beta}2-Adrenergic Receptor Gene and Desensitization in Human Airway Smooth Muscle
Am. J. Respir. Crit. Care Med., December 1, 2000; 162(6): 2117 - 2124.
[Abstract] [Full Text]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
V. P. Krymskaya, M. J. Orsini, A. J. Eszterhas, K. C. Brodbeck, J. L. Benovic, R. A. Panettieri Jr., and R. B. Penn
Mechanisms of Proliferation Synergy by Receptor Tyrosine Kinase and G Protein-Coupled Receptor Activation in Human Airway Smooth Muscle
Am. J. Respir. Cell Mol. Biol., October 1, 2000; 23(4): 546 - 554.
[Abstract] [Full Text]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
C. K. Billington, I. P. Hall, S. J. Mundell, J.-L. Parent, R. A. Panettieri Jr., J. L. Benovic, and R. B. Penn
Inflammatory and Contractile Agents Sensitize Specific Adenylyl Cyclase Isoforms in Human Airway Smooth Muscle
Am. J. Respir. Cell Mol. Biol., November 1, 1999; 21(5): 597 - 606.
[Abstract] [Full Text]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
M. J. Orsini, V. P. Krymskaya, A. J. Eszterhas, J. L. Benovic, R. A. Panettieri Jr., and R. B. Penn
MAPK superfamily activation in human airway smooth muscle: mitogenesis requires prolonged p42/p44 activation
Am J Physiol Lung Cell Mol Physiol, September 1, 1999; 277(3): L479 - L488.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
Y. Amrani, A. L. Lazaar, and R. A. Panettieri Jr.
Up-Regulation of ICAM-1 by Cytokines in Human Tracheal Smooth Muscle Cells Involves an NF-{kappa}B-Dependent Signaling Pathway That Is Only Partially Sensitive to Dexamethasone
J. Immunol., August 15, 1999; 163(4): 2128 - 2134.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
V. P. Krymskaya, R. B. Penn, M. J. Orsini, P. H. Scott, R. J. Plevin, T. R. Walker, A. J. Eszterhas, Y. Amrani, E. R. Chilvers, and R. A. Panettieri Jr.
Phosphatidylinositol 3-kinase mediates mitogen-induced human airway smooth muscle cell proliferation
Am J Physiol Lung Cell Mol Physiol, July 1, 1999; 277(1): L65 - L78.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
J. Haynes Jr., B. Obiako, P. Babal, and T. Stevens
5-(N-ethylcarboxamido)adenosine desensitizes the A2b-adenosine receptor in lung circulation
Am J Physiol Heart Circ Physiol, June 1, 1999; 276(6): H1877 - H1883.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
R. B. Penn, J.-L. Parent, A. N. Pronin, R. A. Panettieri Jr., and J. L. Benovic
Pharmacological Inhibition of Protein Kinases in Intact Cells: Antagonism of Beta Adrenergic Receptor Ligand Binding by H-89 Reveals Limitations of Usefulness
J. Pharmacol. Exp. Ther., February 1, 1999; 288(2): 428 - 437.
[Abstract] [Full Text]

Home page
 J. Biol. Chem.Home page
R. B. Penn, R. M. Pascual, Y.-M. Kim, S. J. Mundell, V. P. Krymskaya, R. A. Panettieri Jr., and J. L. Benovic
Arrestin Specificity for G Protein-coupled Receptors in Human Airway Smooth Muscle
J. Biol. Chem., August 24, 2001; 276(35): 32648 - 32656.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Crit. Care Med.
Copyright © 1998 American Thoracic Society.