Institute of Reconstructive Neurobiology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
Exp Neurol. 2011 Dec;232(2):185-94. doi: 10.1016/j.expneurol.2011.08.022. Epub 2011 Aug 30.
Store-operated Ca(2+) entry (SOCE) over the plasma membrane is activated by depletion of intracellular Ca(2+) stores and has only recently been shown to play a role in CNS processes like synaptic plasticity. However, the direct effect of SOCE on the excitability of neuronal networks in vitro and in vivo has never been determined. We confirmed the presence of SOCE and the expression of the calcium sensors STIM1 and STIM2, which convey information about the calcium load of the stores to channel proteins at the plasma membrane, in neurons and astrocytes. Inhibition of SOCE by pharmacological agents 2-APB and ML-9 reduced the steady-state neuronal Ca(2+) concentration, reduced network activity, and increased synchrony of primary neuronal cultures grown on multi-electrode arrays, which prompted us to elucidate the relative expression of STIM proteins in conditions of pathologic excitability. Both proteins were increased in brains of chronic epileptic rodents and strongly expressed in hippocampal specimens from medial temporal lobe epilepsy patients. Pharmacologic inhibition of SOCE in chronic epileptic hippocampal slices suppressed interictal spikes and rhythmized epileptic burst activity. Our results indicate that SOCE modulates the activity of neuronal networks in vitro and in vivo and delineates SOCE as a potential drug target.
储存操作的钙离子内流（SOCE）通过细胞内钙储存的耗竭而被激活，最近才被证明在中枢神经系统过程中发挥作用，如突触可塑性。然而，SOCE 对体外和体内神经元网络兴奋性的直接影响从未被确定。我们在神经元和星形胶质细胞中证实了 SOCE 的存在和钙传感器 STIM1 和 STIM2 的表达，STIM1 和 STIM2 将关于储存钙负荷的信息传递给质膜上的通道蛋白。通过药理学试剂 2-APB 和 ML-9 抑制 SOCE 降低了神经元的稳态钙浓度，降低了网络活动，并增加了在多电极阵列上生长的原代神经元培养物的同步性，这促使我们阐明在病理兴奋性条件下 STIM 蛋白的相对表达。这两种蛋白质在慢性癫痫啮齿动物的大脑中增加，并在颞叶内侧癫痫患者的海马标本中强烈表达。在慢性癫痫海马切片中抑制 SOCE 的药理学抑制抑制了发作间期的尖峰和节律化的癫痫爆发活动。我们的结果表明，SOCE 调节体外和体内神经元网络的活性，并将 SOCE 描绘为一个潜在的药物靶点。
