Effect of proinflammatory cytokines on regulation of sarcoplasmic reticulum Ca2+ reuptake in human airway smooth muscle

Venkatachalem Sathish, Michael A. Thompson, Jeffrey P. Bailey, Christina M. Pabelick, Y. S. Prakash, Gary C. Sieck

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

Airway inflammation leads to increased intracellular Ca2+ ([Ca2+]i) levels in airway smooth muscle (ASM) cells. Sarcoplasmic reticulum Ca2+ release and reuptake are key components of ASM [Ca2+]i regulation. Ca2+ reuptake occurs via sarcoendoplasmic reticulum Ca2+ ATPase (SERCA) and is regulated by the inhibitory protein phospholamban (PLB) in many cell types. In human ASM, we tested the hypothesis that inflammation increases PLB, thus inhibiting SERCA function, and leading to maintained [Ca2+]i levels. Surprisingly, we found that human ASM does not express PLB protein (although mRNA is detectable). Overnight exposure to the proinflammatory cytokines TNFα and IL-13 did not induce PLB expression, raising the issue of how SERCA is regulated. We then found that direct SERCA phosphorylation (via CaMKII) occurs in human ASM. In fura-2-loaded human ASM cells, we found that the CaMKII antagonist KN-93 significantly slowed the rate of fall of [Ca 2+]i transients induced by ACh or bradykinin (in zero extracellular Ca2+), suggesting a role for CaMKII-mediated SERCA regulation. SERCA expression was decreased by cytokine exposure, and the rate of fall of [Ca2+]i transients was slowed in cells exposed to TNFα and IL-13. Cytokine effects on Ca2+ reuptake were unaffected by additional exposure to KN-93. These data indicate that in human ASM, SERCA is regulated by mechanisms such as CaMKII and that airway inflammation maintains [Ca2+]i levels by decreasing SERCA expression and slowing Ca2+ reuptake.

Original languageEnglish (US)
Pages (from-to)L26-L34
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume297
Issue number1
DOIs
StatePublished - Jul 1 2009

Keywords

  • Calmodulin
  • Calmodulin kinase
  • Interleukin-13
  • Sarcoendoplasmic reticulum Ca ATPase
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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