Impaired relaxation of airway smooth muscle in mice lacking the actin-binding protein gelsolin

Maya Mikami, Yi Zhang, Jennifer Danielsson, Tiarra Joell, Hwan Mee Yong, Elizabeth Townsend, Seema Khurana, Steven S. An, Charles W. Emala

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Diverse classes of ligands have recently been discovered that relax airway smooth muscle (ASM) despite a transient increase in intracellular calcium concentrations ([Ca2+]i). However, the cellular mechanisms are not well understood. Gelsolin is a calcium-activated actin-severing and -capping protein found in many cell types, including ASM cells. Gelsolin also binds to phosphatidylinositol 4,5-bisphosphate, making this substrate less available for phospholipase Cβ-mediated hydrolysis to inositol triphosphate and diacylglycerol. We hypothesized that gelsolin plays a critical role in ASM relaxation and mechanistically accounts for relaxation by ligands that transiently increase [Ca2+]i. Isolated tracheal rings from gelsolin knockout (KO) mice showed impaired relaxation to both a β-agonist and chloroquine, a bitter taste receptor agonist, which relaxes ASM, despite inducing transiently increased [Ca2+]i. A single inhalation of methacholine increased lung resistance to a similar extent in wild-type and gelsolin KO mice, but the subsequent spontaneous relaxation was less in gelsolin KO mice. InASMcells derived from gelsolinKOmice, serotonin-induced Gq-coupled activation increased both [Ca2+]i and inositol triphosphate synthesis to a greater extent compared to cells from wild-type mice, possibly due to the absence of gelsolin binding to phosphatidylinositol 4,5-bisphosphate. Single-cell analysis showed higher filamentous:globular actin ratio at baseline and slower cytoskeletal remodeling dynamics in gelsolin KO cells. Gelsolin KO ASM cells also showed an attenuated decrease in cell stiffness to chloroquine and flufenamic acid. These findings suggest that gelsolin plays a critical role in ASM relaxation and that activation of gelsolin may contribute to relaxation induced by ligands that relax ASM despite a transient increase in [Ca2+]i.

Original languageEnglish (US)
Pages (from-to)628-636
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Volume56
Issue number5
DOIs
StatePublished - May 2017
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Keywords

  • Actin cytoskeleton
  • Bitter taste receptor agonist
  • Cell stiffness
  • FlexiVent
  • Smooth muscle relaxation

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