[Frontiers in Bioscience 15, 750-764, January 1, 2010]

Mechanisms of airway smooth muscle relaxation induced by beta2-adrenergic agonists

Philippe Delmotte1, Anna-Rebekka Ressmeyer1, Yan Bai1, Michael J. Sanderson1

1Department of Physiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester MA, 01655

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Beta2-adrenergic agonists
4. Fundamentals of airway smooth muscle contraction
4.1. Airway physiology revealed with lung slices
5. Calcium signaling in airway smooth muscle cells
5.1. Mechanisms of agonist-induced calcium oscillations
5.1.1. Contribution of inositol trisphosphate receptors
5.1.2. Contribution of ryanodine receptors
5.1.3. Regulation of the calcium oscillation frequency
5.2. Calcium sensitivity of airway smooth muscle cells
6. Mechanisms of airway smooth muscle relaxation
6.1. The influence of calcium influx and calcium stores
6.2. Sensitivity of the inositol trisphosphate receptor
6.3. Airway relaxation induced by nitric oxide
6.4. Airway relaxation induced by beta2-adrenergic agonists
6.4.1. Effects of beta2-adrenergic agonists on calcium oscillations
6.4.2. Effects of beta2-adrenergic agonists on receptor desensitization
6.4.3. Effect of enantiomers of beta2-adrenergic agonists on airway relaxation
6.4.4. Effects of beta2-adrenergic agonists on calcium sensitivity
7. Summary and perspective
8. Acknowledgments
9. References

1. ABSTRACT

Airway smooth muscle cell (ASMC) contraction is regulated by myosin phosphorylation to control actin-myosin cross-bridge activity. Myosin phosphorylation is determined by the antagonistic activity of myosin light chain (MLC) kinase (MLCK) and phosphatase (MLCP). MLCK activity is increased by increases in intracellular Ca2+ concentration ((Ca2+)i) associated with Ca2+ oscillations. MLCP activity is decreased by phosphorylation of MLCP or accessory proteins by kinases, including Rho-kinase or protein kinase C. During agonist-induced ASMC contraction, these 2 pathways are simultaneously activated. Because MLCP activity is often independent of (Ca2+)i, changes in MLCP activity can alter ASMC tone at a constant (Ca2+)i; a behavior termed Ca2+ sensitivity. In asthma, airway hyperresponsiveness (AHR) may result from an increase in the Ca2+-dependent contractile mechanisms and/or the Ca2+ sensitivity of ASMCs. Conversely, inhalation of beta2-adrenergic agonists induce airway relaxation by simultaneously slowing the Ca2+ oscillations and reducing the Ca2+ sensitivity of ASMCs. However, the action of beta2-adrenergic agonists varies with species. Consequently, the development of beta2-adrenergic agonists requires a characterization of their action in human airways.