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The generation of acetylcholine-induced asynchronous Ca²⁺ waves and their role in airway smooth muscle Dai, Jiazhen Minnie


Agonist-stimulated repetitive asynchronous Ca²⁺ waves (ACW) have emerged as ubiquitous Ca²⁺ signals in airway smooth muscle cells. Even though the role of this type of Ca²⁺ signal in airway smooth muscle (ASM) has yet to be defined, it is likely that ACW are involved in the regulation of airway constriction due to the significance of Ca²⁺ in ASM contraction. This thesis focuses on: (1) the primary function of ACW and (2) the signaling pathway(s) underlying agonist-induced ACW in intact ASM. Employing confocal imaging of Ca²⁺-sensitive dyes, we found that ACh elicits recurring intracellular Ca²⁺ waves in cells of the intact porcine tracheal and more importantly human bronchial muscle bundle. These Ca²⁺ waves were not synchronized between neighboring cells. Simultaneous measurement of intracellular Ca²⁺ concentration ([Ca²⁺]i ) and isometric contraction indicates that induction of these ACW was temporally associated with development of force by the muscle bundles. By comparing the concentration dependence of force generation and the parameters characterizing ACW, we found that the concentration-dependent increase in ACh-induced force development by the ASM bundle is achieved by differential recruitment of cells to initiate Ca²⁺ waves followed by enhancement in the frequency of ACW and elevation of interspike [Ca²⁺ ]i once the cells are recruited. Furthermore, pharmacological characterization of the mechanism of ACh-induced ACW revealed that they are a result of repetitive cycles of sarcoplasmic reticulum (SR) Ca²⁺ release via ryanodine-sensitive Ca²⁺ release channels followed by refilling of the SR via sarco(endo)plasmic reticulum Ca²⁺ ATPase. Plasmalemmal Ca²⁺ entry via the reverse-mode Na⁺/Ca²⁺ exchange coupled with the non-selective cation permeable receptor-operated channels/store-operated channels, and to a lesser extent via the L-type voltage-gated Ca²⁺ channels is involved in replenishing the SR and supporting the ongoing ACW. Given the significance of ASM in the pathogenesis of airway diseases such as asthma, these findings provide insights into the regulation of ASM contraction and potential therapeutic targets for the management of these diseases.

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