FKBP12.6 and cADPR regulation of Ca2+ release in smooth muscle cells.
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.
Wang
Yong-Xiao
YX
Center for Cardiovascular Sciences, Albany Medical College, Albany, New York 12208, USA. wangy@mail.amc.edu
Zheng
Yun-Min
YM
Mei
Qi-Bing
QB
Wang
Qinq-Song
QS
Collier
Mei Lin
ML
Fleischer
Sidney
S
Xin
Hong-Bo
HB
Kotlikoff
Michael I
MI
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D036563:Cyclic ADP-Ribose / Q000378:metabolism*; D006736:Horses; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*; D014132:Trachea / Q000166:cytology
D002712:Chlorides; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; D036563:Cyclic ADP-Ribose; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B; D000109:Acetylcholine; D002118:Calcium; D016559:Tacrolimus