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

Front Biosci (Landmark Ed). 2010 Jan 1;15:750-64. doi: 10.2741/3644.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Agonists / pharmacology*
  • Animals
  • Calcium / metabolism
  • Calcium Signaling / drug effects
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • Lung / metabolism
  • Lung / physiology*
  • Models, Biological
  • Muscle Relaxation / drug effects*
  • Muscle, Smooth / cytology
  • Muscle, Smooth / metabolism
  • Muscle, Smooth / physiology*
  • Myosin-Light-Chain Kinase / metabolism
  • Myosin-Light-Chain Phosphatase / metabolism
  • Myosins / metabolism
  • Nitric Oxide / metabolism
  • Phosphorylation / drug effects
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • rho-Associated Kinases / metabolism

Substances

  • Adrenergic beta-Agonists
  • Inositol 1,4,5-Trisphosphate Receptors
  • Ryanodine Receptor Calcium Release Channel
  • Nitric Oxide
  • rho-Associated Kinases
  • Myosin-Light-Chain Kinase
  • Myosin-Light-Chain Phosphatase
  • Myosins
  • Calcium