Ca2+ Dynamics and Ca2+ Sensitization in the Regulation of Airway Smooth Muscle Tone

  • Kume H
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Airway smooth muscle tone is ultimately generated by phosphorylation of myosin light chain, which is regulated by the balance between concentrations of Ca 2+ and sensitivity to Ca 2+ in the cytosolic side. The former is due to the Ca 2+ influx passing through ion channels (Ca 2+ dynamics), leading to activation of myosin light chain kinase, and the latter is due to Rho-kinase (Ca 2+ sensitization), leading to the inacti‐ vation of myosin phosphatase. Alterations to contractility and to the proliferative phenotype, which are influenced by Ca 2+ dynamics and Ca 2+ sensitization, are in‐ volved in the pathophysiology of asthma and chronic obstructive pulmonary dis‐ ease (COPD). Ca 2+ dynamics are mainly due to store-operated capacitative Ca 2+ influx and receptor-operated Ca 2+ influx, and partly due to L-type voltage-depend‐ ent Ca 2+ (VDC) channels. Large-conductance Ca 2+ -activated K + (K Ca, BK Ca, Maxi-K +) channels are activated by G s connected to β 2 -adrenoceptors, whereas these channels are inhibited by G i connected to M 2 muscarinic receptors. VDC channel activity regulated by K Ca channels contributes to not only functional antagonism between β 2 -adrenoceptors and muscarinic receptors but also to synergistic effects between β 2 -adrenoceptor agonists and muscarinic receptor antagonists. Moreover, an in‐ crease in Ca 2+ influx via the K Ca /VDC channel linkage causes airflow limitation and β 2 -adrenergic desensitization. In contrast, an increase in sensitivity to Ca 2+ via Rho-kinase causes airflow limitation, airway hyperresponsiveness, β 2 -adrenergic desen‐ sitization, and airway remodeling. These airway disorders are characteristic features of asthma and COPD. K Ca channels are regulated by trimeric G proteins (G s , G i), and Rho-kinase is regulated by a monomeric G protein (RhoA). Therefore, Ca 2+ dynamics due to G proteins/K Ca /VDC channel linkage and Ca 2+ sensitization due to RhoA/Rho-kinase processes are therapeutic targets for these diseases.




Kume, H. (2015). Ca2+ Dynamics and Ca2+ Sensitization in the Regulation of Airway Smooth Muscle Tone. In Muscle Cell and Tissue. InTech.

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