近日,，PLoS ONE發(fā)表了英國布里斯托大學(xué)和曼徹斯特大學(xué)研究人員的成果，揭開了心力衰竭的機制,，發(fā)現(xiàn)兩種蛋白質(zhì)調(diào)節(jié)心臟細胞內(nèi)鈣的釋放,，為避免這種風(fēng)險情況提供了新的可能。
心力衰竭患者由于心臟細胞中鈣離子未得到正確控制并因此而引發(fā)的不規(guī)則心跳,，從而面臨著意外死亡的風(fēng)險,。這項研究由布里斯托爾大學(xué)生理與藥理學(xué)院的研究人員完成，他們揭示了兩種獨立卻極其相似的蛋白質(zhì)共同調(diào)節(jié)心臟細胞中鈣離子濃度的機制以及這種雙重調(diào)節(jié)方式在心力衰竭中的減弱方式,。
在健康人的心臟細胞中，鈣離子從細胞內(nèi)的儲存中釋放出來并形成心臟的有力跳動,，從而將血液泵至全身,。鈣離子通過叫做“蘭尼堿受體(RyR)通道”的特定通路在恰當(dāng)?shù)臅r間以合適的量進行釋放。而在心力衰竭患者中,，細胞內(nèi)的鈣釋放會變得沒有規(guī)律,，從而導(dǎo)致心跳節(jié)奏異常。
通過將單獨的RyR通道從心臟細胞中移除并整合至人工膜中,，研究人員對流經(jīng)單個通道分子的微量鈣離子流進行了測定。他們發(fā)現(xiàn),，兩種分別稱為FKBP12和FKBP12.6的蛋白質(zhì)緊密地結(jié)合在RyR通道上,，并改變著流經(jīng)它們的鈣離子的量。
他們的研究顯示,，F(xiàn)KBP12與FKBP12.6蛋白非常相似，但是在功能上完全不同,。FKBP12增加通過RyR的鈣離子流，而FKBP12.6起著阻礙FKBP12這種效果的作用,。在心力衰竭患者中,，這種雙重調(diào)節(jié)似乎遭受了破壞。
該校的Rebecca Sitsapesan博士說：“心臟及循環(huán)系統(tǒng)疾病是英國人口死亡的一個主要原因,，每年造成大約191000人死亡,，是總死亡人數(shù)的三分之一。這些新的發(fā)現(xiàn)非常重要,，因為我們可以利用這些信息為心力衰竭患者開發(fā)新的療法,，以減少意外死亡的風(fēng)險,。”（生物谷Bioon.com）
doi:10.1371/journal.pone.0031956
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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.
