Dissociation of FK506-binding protein 12.6 kD from ryanodine receptor in bronchial smooth muscle cells in airway hyperresponsiveness in asthma

Ying Du, Jianhong Zhao, Xi Li, Si Jin, Wan Li Ma, Qing Mu, Shuxiang Xu, Jie Yang, Shanshan Rao, Liping Zhu, Jianbao Xin, Peng Cheng Cai, Yunchao Su, Hong Ye

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Airway hyperresponsiveness (AHR) in asthma is predominantly caused by increased sensitivity of bronchial smooth muscle cells (BSMCs) to stimuli. The sarcoplasmic reticulum (SR)-Ca21 release channel, known as ryanodine receptor (RyR), mediates the contractive response of BSMCs to stimuli. FK506-binding protein 12.6 kD (FKBP12.6) stabilizes the RyR2 channel in a closed state. However, the interaction of FKBP12.6 with RyR2 in AHR remains unknown. This study examined the interaction of FKBP12.6 with RyR2 in BSMCs inAHRof asthma. The interaction of FKBP12.6 with RyR2 and FKBP12.6 expression was determined in a rat asthma model and in BSMCs treated with inflammatory cytokines. The calcium responses to contractile agonists were determined in BSMCs with overexpression and knockdown of FKBP12.6. Asthmatic serum, IL-5, IL-13, and TNF-a enhance the calcium response of BSMCs to contractile agonists and cause dissociation of FKBP12.6 from RyR2 and a decrease in FKBP12.6 gene expression in BSMCs in culture and in ovalbumin (OVA)-sensitized and -challenged rats. Knockdown of FKBP12.6 inBSMCscauses a decrease in the association of RyR2 with FKBP12.6 and an increase in the calcium response of BSMCs. Overexpression of FKBP12.6 increases the association of FKBP12.6 with RyR2, decreases the calcium response of BSMCs, and normalizes airway responsiveness in OVA-sensitized and -challenged rats. Dissociation of FKBP12.6 from RyR2 in BSMCs is responsible for the increased calcium response contributing to AHR in asthma. Manipulating the interaction of FKBP12.6 with RyR2 might be a novel and useful treatment for asthma.

Original languageEnglish (US)
Pages (from-to)398-408
Number of pages11
JournalAmerican journal of respiratory cell and molecular biology
Volume50
Issue number2
DOIs
StatePublished - Feb 1 2014

Keywords

  • Airway hyperresponsiveness
  • Asthma
  • Calcium
  • FKBP12.6
  • RyR2

ASJC Scopus subject areas

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

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