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FKBP12-6 Knockout Increases Ryanodine Receptors Open Probability during b-adrenergic Stimulation in Mice Cardiac Myocytes

【摘要】:正FK506 binding protein 12.6(FK-BP12.6) is the protein in the ryanodine receptor complex,but its function is controversial in different reported work.Some conclude that FK-BP12.6 stabilizes ryanodine receptors(RyRs) but some conclude that it has no effect on RyRs.The published work of FKBP12.6 effect on RyRs is demonstrated by lipid bilayer experiment,which destroys the in situ environment around FKBP12. 6 and RyRs.Here,we employed two methods to test FKBP12.6 function directly in RyR complex in intact cardiac myocytes.First,using loose-seal patch clamp combined with confocal imaging,we gave the cell membrane a local depolarization to~0mV just below the pipette,at the same time recorded the Ca~(2+) fluorescent signals,as sparklet from L-type calcium channel(LCC) and spark from RyRs.We found that the spark amplitude was decreased and the LCC-RyR coupling latency was shortened in FKBP12.6 knockout mice (KO).Analyzation of spark flux revealed that the quantal nature of RyR Ca~(2+) release observed in WT was diminished in KO,indicating that the coupled state of RyR Ca~(2+) release channel was destroyed when FKBP12.6 was dissociated from RyR complex.When using isoproterenol(ISO), a b-adrenergic receptors agonist,we found that the LCC-RyR coupling latency in KO myocytes was much shorter,more sparks and Ca~(2+) waves occurred compared with ISO treated WT myocytes. We also certified the above results in rat cardiac myocytes pharmacologically,using FK506,the drug proved to dissociate FKBP12.6 from RyR complex.Second,using whole cell patch clamp with confocal imaging,we gave cells a high voltage depolarization(+ 160mV) to make sure all the available LCCs were open,then repolarized to different voltages(-70-120 mV) to make different i_(Ca).We found that FK506 with ISO together induced higher Ca~(2+) transient, whatever i_(Ca) was small(at higher repolarization voltages) or big(at lower repolarization voltages). Together,we conclude that FKBP12.6 is important to maintain the quantal nature of RyR Ca~(2+) release channel,stabilizing it during diastole and make it act synchronically during systole,to ensure that RyRs open and close at proper time. The above may explain that people with either RyR or FKBP12.6 mutations affecting the interaction between the two proteins are well-living, but may suffer from catecholaminergic polymorphic ventricular tachycardia or sudden cardiac death when b-adrenergic nerve is activated.

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