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

Airway smooth muscle tone is ultimately generated by phosphorylation of myosin light chain, which is regulated by the balance between concentrations of Ca2+ and sensitivity to Ca2+ in the cytosolic side. The former is due to the Ca2+ influx passing through ion channels (Ca2+ dynamics), leading to activation of myosin light chain kinase, and the latter is due to Rho-kinase (Ca2+ sensitization), leading to the inacti‐ vation of myosin phosphatase. Alterations to contractility and to the proliferative phenotype, which are influenced by Ca2+ dynamics and Ca2+ sensitization, are in‐ volved in the pathophysiology of asthma and chronic obstructive pulmonary dis‐ ease (COPD). Ca2+ dynamics are mainly due to store-operated capacitative Ca2+ influx and receptor-operated Ca2+ influx, and partly due to L-type voltage-depend‐ ent Ca2+ (VDC) channels. Large-conductance Ca2+-activated K+ (KCa, BKCa, Maxi-K+) channels are activated by Gs connected to β2-adrenoceptors, whereas these channels are inhibited by Gi connected to M2 muscarinic receptors. VDC channel activity regulated by KCa channels contributes to not only functional antagonism between β2-adrenoceptors and muscarinic receptors but also to synergistic effects between β2-adrenoceptor agonists and muscarinic receptor antagonists. Moreover, an in‐ crease in Ca2+ influx via the KCa/VDC channel linkage causes airflow limitation and β2-adrenergic desensitization. In contrast, an increase in sensitivity to Ca2+ via Rhokinase causes airflow limitation, airway hyperresponsiveness, β2-adrenergic desen‐ sitization, and airway remodeling. These airway disorders are characteristic features of asthma and COPD. KCa channels are regulated by trimeric G proteins (Gs, Gi), and Rho-kinase is regulated by a monomeric G protein (RhoA). Therefore, © 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ca2+ dynamics due to G proteins/KCa/VDC channel linkage and Ca2+ sensitization due to RhoA/Rho-kinase processes are therapeutic targets for these diseases.