Airway hyperresponsiveness (AHR) in
asthma is predominantly caused by increased sensitivity of bronchial smooth muscle cells (BSMCs) to stimuli. The sarcoplasmic reticulum (SR)-Ca(2+) 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 in AHR of
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-α 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 in BSMCs causes 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.