FKBP12 Activates the Cardiac Ryanodine Receptor Ca²⁺-Release Channel and Is Antagonised by FKBP12.6

Elena Galfré, Samantha J. Pitt, Elisa Venturi, Mano Sitsapesan, Nathan R. Zaccai, Krasimira Tsaneva-Atanasova, Stephen O'Neill, Rebecca Sitsapesan

Changes in FKBP12.6 binding to cardiac ryanodine receptors (RyR2) are implicated in mediating disturbances in Ca²⁺-homeostasis in heart failure but there is controversy over the functional effects of FKBP12.6 on RyR2 channel gating. We have therefore investigated the effects of FKBP12.6 and another structurally similar molecule, FKBP12, which is far more abundant in heart, on the gating of single sheep RyR2 channels incorporated into planar phospholipid bilayers and on spontaneous waves of Ca²⁺-induced Ca²⁺-release in rat isolated permeabilised cardiac cells. We demonstrate that FKBP12 is a high affinity activator of RyR2, sensitising the channel to cytosolic Ca²⁺, whereas FKBP12.6 has very low efficacy, but can antagonise the effects of FKBP12. Mathematical modelling of the data shows the importance of the relative concentrations of FKBP12 and FKBP12.6 in determining RyR2 activity. Consistent with the single-channel results, physiological concentrations of FKBP12 (3 µM) increased Ca²⁺-wave frequency and decreased the SR Ca²⁺-content in cardiac cells. FKBP12.6, itself, had no effect on wave frequency but antagonised the effects of FKBP12.

We provide a biophysical analysis of the mechanisms by which FK-binding proteins can regulate RyR2 single-channel gating. Our data indicate that FKBP12, in addition to FKBP12.6, may be important in regulating RyR2 function in the heart. In heart failure, it is possible that an alteration in the dual regulation of RyR2 by FKBP12 and FKBP12.6 may occur. This could contribute towards a higher RyR2 open probability, ‘leaky’ RyR2 channels and Ca²⁺-dependent arrhythmias.

• 以上资料由西亚试剂：http://www.xiyashiji.com/ 提供此产品的详细信息如密度,含量,分子式,分子量等均可在西亚官网查询   
• 相关产品如汞乙酸汞氯化汞氧化汞碘化汞硫酸汞硝酸汞溴化汞硝酸亚汞氯化亚汞乙酸苯汞碘化汞钾硫氰酸汞氯化氨基汞三氯生三氯氧磷三氯乙烯水合氯醛三氯化磷三氯化钌三氯化钛三氯化铱三氯化铑三氯硫磷三氯乙烷三氯甲烷三氯卡班TCC1,3,5-三氯苯1,2,4-三氯苯1,2,3-三氯苯无水氯化铝三氯乙酸酐三氯乙酸钠碘甲烷二碘甲烷三碘甲烷 三氟碘甲烷硫酸二甲酯氯磺酸苯硫酚苯硫酚钠3-氨基苯硫酚2,6-二氯苯硫酚2,4-二氯苯硫酚2,5-二氯苯硫酚2-甲氧基苯硫酚2-氯乙醇 等均有销售.欢迎订购