IP3 receptor-dependent Ca2+ release modulates excitation-contraction coupling in rabbit ventricular myocytes
IP3 receptor-dependent Ca2+ release modulates excitation-contraction coupling in rabbit ventricular myocytes
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DOI：
10.1152/ajpheart.01155.2007
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发表时间：
2008-02-01
影响因子：
4.8
通讯作者：
Blatter, Lothar A.
中科院分区：
文献类型：
--
作者：
Domeier, Timothy L.;Zima, Aleksey V.;Blatter, Lothar A.
肌醇1,4,5-三磷酸（IP3）受体（IP3R）依赖的Ca2+信号对心房心肌的兴奋-收缩偶联（ECC）有积极的肌力作用，但也有致心律失常的作用。ip3r依赖性肌浆网（SR） Ca2+释放在心室心肌ECC中的作用仍然存在争议。在此，我们研究了该信号通路在兔心室肌细胞ECC中的作用。来自心室肌细胞的蛋白质免疫印迹显示，2型和3型IP3R的表达水平相似，比心房肌细胞低3.5倍。在通透性肌细胞中，直接施用IP3 （10 μ M）可使Ca2+火花频率瞬间增加21% （P < 0.05）。这种增加伴随着火花幅度下降13% （P < 0.05）和SR Ca2+负荷下降7% (P < 0.05)，并被IP3R拮抗剂2-氨基乙氧基二苯硼酸酯（2-APB, 20 μ M）和肝素（0.5 mg/ml）抑制。在完整肌细胞中，内皮素-1 （100 nM）刺激IP3产生，引起动作电位诱导（0.5 Hz，场刺激）Ca2+瞬态振幅增加38% （P < 0.05）。这种作用被IP3R拮抗剂2- apb （2 μ M）或通过腺病毒表达IP3亲和力陷阱缓冲细胞IP3而消除。综上所述，这些数据表明，在兔心室肌细胞中，ip3r依赖性Ca2+释放通过ryanodine受体簇促进Ca2+释放，对ECC具有正性肌力作用。
Inositol 1,4,5-trisphosphate (IP3) receptor (IP3R)-dependent Ca2+ signaling exerts positive inotropic, but also arrhythmogenic, effects on excitation-contraction coupling (ECC) in the atrial myocardium. The role of IP3R-dependent sarcoplasmic reticulum (SR) Ca2+ release in ECC in the ventricular myocardium remains controversial. Here we investigated the role of this signaling pathway during ECC in isolated rabbit ventricular myocytes. Immunoblotting of proteins from ventricular myocytes showed expression of both type 2 and type 3 IP3R at levels similar to 3.5-fold less than in atrial myocytes. In permeabilized myocytes, direct application of IP3 (10 mu M) produced a transient 21% increase in the frequency of Ca2+ sparks (P < 0.05). This increase was accompanied by a 13% decrease in spark amplitude (P < 0.05) and a 7% decrease in SR Ca2+ load (P < 0.05) and was inhibited by IP3R antagonists 2-aminoethoxydiphenylborate (2-APB; 20 mu M) and heparin (0.5 mg/ml). In intact myocytes endothelin-1 (100 nM) was used to stimulate IP3 production and caused a 38% (P < 0.05) increase in the amplitude of action potential-induced (0.5 Hz, field stimulation) Ca2+ transients. This effect was abolished by the IP3R antagonist 2-APB (2 mu M) or by using adenoviral expression of an IP3 affinity trap that buffers cellular IP3. Together, these data suggest that in rabbit ventricular myocytes IP3R-dependent Ca2+ release has positive inotropic effects on ECC by facilitating Ca2+ release through ryanodine receptor clusters.