Calcium Signalling Among Non-Neuronal Brain Cells

非神经元脑细胞中的钙信号传导

• 批准号: 6529668
• 负责人: Maiken Nedergaard
• 金额: $ 31.3万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6529668
• 关键词: astrocytes; calcium flux; capillary bed; estrogens; gap junctions; guanosinetriphosphatase activating protein; hormone regulation /control mechanism; laboratory rat; meninges; neocortex; neurons; progesterone; vascular endothelium

In previous studies, we have reported that calcium waves among gap junction-coupled glia may form the cellular substrate for spreading depression in vivo. Recently, we have noted that calcium waves initiated in astrocytes in slices can propagate to brain endothelial and meningeal cells; all of these cell types express connexin43, which may allow their mutual heterotypic syncytial interaction through homotypic gap junctions. On this basis, we propose to test the hypothesis that astrocytic calcium waves may thereby invade the brain by propagating along the capillary vasculature, as well as through the astrocytic syncytium. These experiments will test the possibility that endothelial calcium waves may follow the venular endothelium to invade the meningeal vasculature, thereby recruiting both meningeal cells and trigeminal sensory afferents. This proposed pathway, by bypassing and traversing the restrictive barrier of the pia limitans, would permit the recruitment of both the meningeal vasculature and its trigeminal sensory afferents into parenchymal waves of spreading depression. We propose here that this scenario might operationally model the initiation of migraine headache in adults. In parallel experiments, we will also follow-up our recent observation of a steroid-induced accentuation of astrocytic calcium signaling, by asking whether calcium signaling among non-neuronal brain cell types may be modulated by gonadal steroids. In particular, we seek to determine whether the cyclical female hormones estrogen and progesterone potentiate signaling from astrocytes to endothelial cells, and if so, whether the likelihood of meningovascular recruitment into a parenchymal calcium wave is thereby increased. This pathway might account for much of the symptomatology of migraine headache, while steroidal accentuation of calcium signaling might account for the cyclicity of migraine occurrence. The long-distance multicellular calcium signaling pathway that we propose, and its attendant hormonal regulation, suggests immediately testable strategies for its abrogation.

在之前的研究中，我们报道了间隙连接偶联胶质细胞中的钙波可能形成体内传播抑郁的细胞底物。最近，我们注意到在星形胶质细胞中引发的钙波可以传播到脑内皮细胞和脑膜细胞；所有这些细胞类型都表达connexin43，这可能允许它们通过同型间隙连接进行异型合胞相互作用。在此基础上，我们提出验证星形细胞钙波可能通过毛细血管以及星形细胞合胞体传播侵入大脑的假设。这些实验将测试内皮钙波可能跟随静脉内皮侵入脑膜脉管系统，从而招募脑膜细胞和三叉神经感觉传入神经的可能性。这一建议的通路，通过绕过和穿越窄脑膜的限制性屏障，将允许脑膜血管及其三叉神经感觉传入神经聚集到弥漫性压抑的实质波中。我们在这里提出，这种情况可能在操作上模拟成人偏头痛的开始。在平行实验中，我们还将通过询问非神经元脑细胞类型中的钙信号是否可能被性腺类固醇调节，来跟踪我们最近观察到的类固醇诱导星形细胞钙信号的强化。特别是，我们试图确定周期性雌性激素雌激素和孕激素是否增强星形胶质细胞到内皮细胞的信号，如果是这样，是否因此增加了脑膜血管募集到实质钙波的可能性。这一途径可能解释了偏头痛的大部分症状，而钙信号的类固醇强化可能解释了偏头痛发生的周期性。我们提出的长距离多细胞钙信号通路及其伴随的激素调节，为其废除提供了立即可测试的策略。