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1 Center for Cardiovascular Sciences, Albany Medical College, Albany, NY, USA
2 Department of Animal Biology, University of Pennsylvania, Philadelphia, PA, USA
3 Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
4 Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA
* To whom correspondence should be addressed. E-mail: mik7{at}cornell.ed.
Intracellular Ca2+ release through ryanodine receptors (RyRs) plays important roles in smooth muscle excitation-contraction coupling, but the underlying regulatory mechanisms are poorly understood. Here we show that FK506 binding protein 12.6 (FKBP12.6) associates with and regulates type-2 RyRs (RyR2) in tracheal smooth muscle. FKBP12.6 binds to RyR2 but not other RyR or IP3 receptors, and FKBP12, known to bind to and modulate skeletal RyRs, does not associated with RyR2. When dialyzed into tracheal myocytes, cyclic ADP-ribose (cADPR) alters spontaneous Ca2+ release at lower concentrations and produces macroscopic Ca2+ release at higher concentrations; neurotransmitter -evoked Ca2+ release is also augmented by cADPR. These actions are mediated through FKBP12.6, since they are inhibited by molar excess of recombinant FKBP12.6 and are not observed in myocytes from FKBP12.6 knockout mice. We also report that force development in FKBP12.6 null mice, observed as a decrease in the concentration/tension relationship of isolated trachealis segments, is impaired. Taken together, these findings point to an important role of the FKBP12.6/RyR2 complex in stochastic (spontaneous) and receptor -mediated Ca2+ release in smooth muscle.
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