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MUSCLE CELL BIOLOGY AND CELL MOTILITY

FKBP12.6 and cADPR regulation of Ca²⁺ release in smooth muscle cells

¹Center for Cardiovascular Sciences, Albany Medical College, Albany, New York 12208; ²Department of Animal Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104; ³Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37235; and ⁴Department of Biomedical Sciences, Cornell University, Ithaca, New York 14853

Submitted 19 March 2003 ; accepted in final form 15 October 2003

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 of 12.6 kDa (FKBP12.6) associates with and regulates type 2 RyRs (RyR2) in tracheal smooth muscle. FKBP12.6 binds to RyR2 but not other RyR or inositol 1,4,5-trisphosphate receptors, and FKBP12, known to bind to and modulate skeletal RyRs, does not associate 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 because 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.

FK506 binding protein 12.6; ryanodine receptor type 2; calcium sparks; calcium-activated chloride currents

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