scholarly journals Integrin and GPCR Crosstalk in the Regulation of ASM Contraction Signaling in Asthma

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Chun Ming Teoh ◽  
John Kit Chung Tam ◽  
Thai Tran
Keyword(s):  
Smooth Muscle ◽  
G Protein ◽  
Molecular Mechanism ◽  
Airway Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Current Knowledge ◽  
Symptom Relief ◽  
Airway Wall ◽  
G Protein Coupled ◽  
Review Current

Airway hyperresponsiveness (AHR) is one of the cardinal features of asthma. Contraction of airway smooth muscle (ASM) cells that line the airway wall is thought to influence aspects of AHR, resulting in excessive narrowing or occlusion of the airway. ASM contraction is primarily controlled by agonists that bind G protein-coupled receptor (GPCR), which are expressed on ASM. Integrins also play a role in regulating ASM contraction signaling. As therapies for asthma are based on symptom relief, better understanding of the crosstalk between GPCRs and integrins holds good promise for the design of more effective therapies that target the underlying cellular and molecular mechanism that governs AHR. In this paper, we will review current knowledge about integrins and GPCRs in their regulation of ASM contraction signaling and discuss the emerging concept of crosstalk between the two and the implication of this crosstalk on the development of agents that target AHR.

scholarly journals Arrestin Specificity for G Protein-coupled Receptors in Human Airway Smooth Muscle

2001 ◽  
Vol 276 (35) ◽  
pp. 32648-32656 ◽  
Author(s):  
Raymond B. Penn ◽  
Rodolfo M. Pascual ◽  
You-Me Kim ◽  
Stuart J. Mundell ◽  
Vera P. Krymskaya ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
G Protein ◽  
Airway Smooth Muscle ◽  
G Protein Coupled Receptors ◽  
Human Airway Smooth Muscle ◽  
Human Airway ◽  
G Protein Coupled

Does the length dependency of airway smooth muscle force contribute to airway hyperresponsiveness?

2013 ◽  
Vol 115 (9) ◽  
pp. 1304-1315 ◽  
Author(s):  
Audrey Lee-Gosselin ◽  
Chris D. Pascoe ◽  
Christian Couture ◽  
Peter D. Paré ◽  
Ynuk Bossé
Keyword(s):  
Smooth Muscle ◽  
Computational Model ◽  
Airway Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Muscle Force ◽  
Morphological Data ◽  
Airway Wall ◽  
Airway Walls ◽  
Computational Analyses ◽  
Human Bronchi

Airway wall remodeling and lung hyperinflation are two typical features of asthma that may alter the contractility of airway smooth muscle (ASM) by affecting its operating length. The aims of this study were as follows: 1) to describe in detail the “length dependency of ASM force” in response to different spasmogens; and 2) to predict, based on morphological data and a computational model, the consequence of this length dependency of ASM force on airway responsiveness in asthmatic subjects who have both remodeled airway walls and hyperinflated lungs. Ovine tracheal ASM strips and human bronchial rings were isolated and stimulated to contract in response to increasing concentrations of spasmogens at three different lengths. Ovine tracheal strips were more sensitive and generated greater force at longer lengths in response to acetylcholine (ACh) and K+. Equipotent concentrations of ACh were approximately a log less for ASM stretched by 30% and approximately a log more for ASM shortened by 30%. Similar results were observed in human bronchi in response to methacholine. Morphometric and computational analyses predicted that the ASM of asthmatic subjects may be elongated by 6.6–10.4% (depending on airway generation) due to remodeling and/or hyperinflation, which could increase ACh-induced force by 1.8–117.8% (depending on ASM length and ACh concentration) and enhance the increased resistance to airflow by 0.4–4,432.8%. In conclusion, elongation of ASM imposed by airway wall remodeling and/or hyperinflation may allow ASM to operate at a longer length and to consequently generate more force and respond to lower concentration of spasmogens. This phenomenon could contribute to airway hyperresponsiveness.

G protein-coupled receptor kinase 5 regulates airway responses induced by muscarinic receptor activation

2004 ◽  
Vol 286 (2) ◽  
pp. L312-L319 ◽  
Author(s):  
J. K. L. Walker ◽  
R. R. Gainetdinov ◽  
D. S. Feldman ◽  
P. K. McFawn ◽  
M. G. Caron ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
G Protein ◽  
Muscarinic Receptor ◽  
Airway Smooth Muscle ◽  
Muscarinic Receptors ◽  
Muscle Relaxation ◽  
Receptor Activation ◽  
Smooth Muscle Relaxation ◽  
Airway Responses ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) transduce extracellular signals into intracellular events. The waning responsiveness of GPCRs in the face of persistent agonist stimulation, or desensitization, is a necessary event that ensures physiological homeostasis. GPCR kinases (GRKs) are important regulators of GPCR desensitization. GRK5, one member of the GRK family, desensitizes central M2 muscarinic receptors in mice. We questioned whether GRK5 might also be an important regulator of peripheral muscarinic receptor responsiveness in the cardiopulmonary system. Specifically, we wanted to determine the role of GRK5 in regulating muscarinic receptor-mediated control of airway smooth muscle tone or regulation of cholinergic-induced bradycardia. Tracheal pressure, heart rate, and tracheal smooth muscle tension were measured in mice having a targeted deletion of the GRK5 gene ( GRK5- /-) and littermate wild-type (WT) control mice. Both in vivo and in vitro results showed that the airway contractile response to a muscarinic receptor agonist was not different between GRK5- /- and WT mice. However, the relaxation component of bilateral vagal stimulation and the airway smooth muscle relaxation resulting from β2-adrenergic receptor activation were diminished in GRK5- /- mice. These data suggest that M2 muscarinic receptor-mediated opposition of airway smooth muscle relaxation is regulated by GRK5 and is, therefore, excessive in GRK5- /- mice. In addition, this study shows that GRK5 regulates pulmonary responses in a tissue- and receptor-specific manner but does not regulate peripheral cardiac muscarinic receptors. GRK5 regulation of airway responses may have implications in obstructive airway diseases such as asthma or chronic obstructive pulmonary disease.

Effect of Halothane on the Guanosine 5′ Triphosphate Binding Activity of G-Protein αiSubunits

2003 ◽  
Vol 99 (1) ◽  
pp. 105-111 ◽  
Author(s):  
John Streiff ◽  
Kristofer Jones ◽  
William J. Perkins ◽  
David O. Warner ◽  
Keith A. Jones
Keyword(s):  
Smooth Muscle ◽  
G Protein ◽  
Airway Smooth Muscle ◽  
Specific Activity ◽  
Binding Activity ◽  
Muscle Membrane ◽  
Receptor Complex ◽  
Gtp Binding ◽  
Smooth Muscle Membrane ◽  
G Protein Coupled

Background Receptor-mediated increases in the force produced by airway smooth muscle are attenuated by anesthetics such as halothane. Guanosine 5'-triphosphate (GTP) binding protein alpha subunits (Galpha(i)) are known to participate in the regulation of force in airway smooth muscle. The authors hypothesized that halothane would inhibit the ability of Galpha(i) subunits to bind a nonhydrolyzable analog of GTP (GTPgammaS). Methods The effect of halothane on both GTPase-specific activity and [35S]GTPgammaS binding were assayed using purified, recombinant Galpha(i1). In separate experiments, [35S]GTPgammaS binding to Galpha(i) in crude airway smooth muscle membrane preparations was assayed using an immunoprecipitation technique in the presence and absence of halothane. Results The steady state GTPase-specific activity of the recombinant Galpha(i1) was 0.033 +/- 0.018 (mean +/- SD) mole P(i) mole Galpha(i1)-1 min-1 under control conditions and 0.035 +/- 0.015 mole P(i) mole Galpha(i1)-1 min-1 in the presence of 1.1 +/- 0.2 mm halothane, a difference that is not significant. The mole fractions of recombinant Galpha(i1) bound to [35S]GTPgammaS were 0.49 +/- 0.02 and 0.60 +/- 0.02 at 10 and 20 min, respectively. The addition of halothane (1.26 +/- 0.07 mm) did not significantly change these values. Halothane did not affect the binding of [35S]GTPgammaS to Galpha(i) subunits in membrane fractions of airway smooth muscle as measured using immunoprecipitation. Validity of the assays was confirmed using suramin, an inhibitor of GTP binding. Conclusion These results suggest that halothane, which inhibits receptor-activated Galpha(i)-coupled pathways in intact airway smooth muscle, must functionally target a component of the G protein-coupled receptor complex other than Galpha(i).

Sign in / Sign up

Export Citation Format

Share Document