AUTHOR=Han Young-Soo , Delmotte Philippe , Sieck Gary C. TITLE=Effects of TNFα on Dynamic Cytosolic Ca2 + and Force Responses to Muscarinic Stimulation in Airway Smooth Muscle JOURNAL=Frontiers in Physiology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2021.730333 DOI=10.3389/fphys.2021.730333 ISSN=1664-042X ABSTRACT=

Previously, we reported that in airway smooth muscle (ASM), the cytosolic Ca²⁺ ([Ca²⁺]_cyt) and force response induced by acetyl choline (ACh) are increased by exposure to the pro-inflammatory cytokine tumor necrosis factor α (TNFα). The increase in ASM force induced by TNFα was not associated with an increase in regulatory myosin light chain (rMLC₂₀) phosphorylation but was associated with an increase in contractile protein (actin and myosin) concentration and an enhancement of Ca²⁺ dependent actin polymerization. The sensitivity of ASM force generation to elevated [Ca²⁺]_cyt (Ca²⁺ sensitivity) is dynamic involving both the shorter-term canonical calmodulin-myosin light chain kinase (MLCK) signaling cascade that regulates rMLC₂₀ phosphorylation and cross-bridge recruitment as well as the longer-term regulation of actin polymerization that regulates contractile unit recruitment and actin tethering to the cortical cytoskeleton. In this study, we simultaneously measured [Ca²⁺]_cyt and force responses to ACh and explored the impact of 24-h TNFα on the dynamic relationship between [Ca²⁺]_cyt and force responses. The temporal delay between the onset of [Ca²⁺]_cyt and force responses was not affected by TNFα. Similarly, the rates of rise of [Ca²⁺]_cyt and force responses were not affected by TNFα. The absence of an impact of TNFα on the short delay relationships between [Ca²⁺]_cyt and force was consistent with the absence of an effect of [Ca²⁺]_cyt and force on rMLC₂₀ phosphorylation. However, the integral of the phase-loop plot of [Ca²⁺]_cyt and force increased with TNFα, consistent with an impact on actin polymerization and, contractile unit recruitment and actin tethering to the cortical cytoskeleton.