Hiroaki Kume

By Hiroaki Kume

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 inactivation of myosin phosphatase. Alterations to contractility and to the proliferative phenotype, which are influenced by Ca2+ dynamics and Ca2+ sensitization, are involved in the pathophysiology of asthma and chronic obstructive pulmonary disease (COPD). Ca2+ dynamics are mainly due to store-operated capacitative Ca2+ influx and receptor-operated Ca2+ influx, and partly due to L-type voltage-dependent 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 increase 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 Rho-kinase causes airflow limitation, airway hyperresponsiveness, β2-adrenergic desensitization, 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, 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.

Part of the book: Muscle Cell and Tissue