Bradykinin-induced astrocyte-neuron signalling: glutamate release is mediated by ROS-activated volume-sensitive outwardly rectifying anion channels
Bradykinin-induced astrocyte-neuron signalling: glutamate release is mediated by ROS-activated volume-sensitive outwardly rectifying anion channels
复制标题
DOI：
10.1113/jphysiol.2008.165084
复制
发表时间：
2009-05-15
影响因子：
5.5
通讯作者：
Okada, Yasunobu
中科院分区：
文献类型：
--
作者：
Liu, Hong-Tao;Akita, Tenpei;Okada, Yasunobu
胶质细胞释放胶质递质，向邻近的神经元和胶质细胞发出信号。先前的研究表明，在缓激肽刺激下，大鼠星形胶质细胞释放谷氨酸，并引起NMDA受体介导的邻近神经元细胞内Ca2+升高。在这里，我们研究了缓激肽如何诱导小鼠星形胶质细胞释放谷氨酸信号到共同培养的邻近神经元。小鼠星形胶质细胞向神经元的信号传导和缓激肽诱导的谷氨酸释放均被阴离子通道阻滞剂4,4'-二异硫氰基二苯乙烯-2,2'-二磺酸（DIDS）和根皮素抑制。谷氨酸释放对4-（2-丁基-6,7-二氯-2-环戊基林丹-1-对5-基）氧丁酸（DCPIB）也很敏感，DCPIB是一种体积敏感的向外整流阴离子通道（VSOR）的特异性阻滞剂。星形胶质细胞，而不是神经元，对缓激肽有反应，激活全细胞Cl-电流。虽然缓激肽刺激的星形胶质细胞没有发生细胞肿胀，但缓激肽激活的电流表现出典型的VSOR特性：向外整流，渗透收缩抑制，对DIDS、根皮素和DCPIB敏感，依赖于细胞内ATP，以及对谷氨酸的渗透性。缓激肽增加小鼠星形胶质细胞内活性氧（ROS）。用ROS清除剂或NAD(P)H氧化酶抑制剂预处理小鼠星形胶质细胞可阻断缓激肽诱导的VSOR激活、谷氨酸释放和星形胶质细胞到神经元的信号传导。相比之下，BAPTA-AM或破伤风神经毒素A预处理均未能抑制缓激肽诱导的谷氨酸释放。因此，小鼠星形胶质细胞在缓激肽刺激下被ROS激活的VSOR作为谷氨酸释放介导星形胶质细胞到神经元信号传导的途径。由于缓激肽是炎症的初始介质，VSOR可能在炎症期间大脑胶质-神经元通讯中发挥作用。
Glial cells release gliotransmitters which signal to adjacent neurons and glial cells. Previous studies showed that in response to stimulation with bradykinin, glutamate is released from rat astrocytes and causes NMDA receptor-mediated elevation of intracellular Ca2+ in adjacent neurons. Here, we investigate how bradykinin-induced glutamate release from mouse astrocytes signals to neighbouring neurons in co-cultures. Astrocyte-to-neuron signalling and bradykinin-induced glutamate release from mouse astrocytes were both inhibited by the anion channel blocker 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) and phloretin. Glutamate release was also sensitive to 4-(2-Butyl-6,7-dichlor-2-cyclopentylindan-1-on-5-yl) oxybutyric acid (DCPIB), a specific blocker of the volume-sensitive outwardly rectifying anion channel (VSOR). Astrocytes, but not neurons, responded to bradykinin with activation of whole-cell Cl- currents. Although astrocytes stimulated with bradykinin did not undergo cell swelling, the bradykinin-activated current exhibited properties typical of VSOR: outward rectification, inhibition by osmotic shrinkage, sensitivity to DIDS, phloretin and DCPIB, dependence on intracellular ATP, and permeability to glutamate. Bradykinin increased intracellular reactive oxygen species (ROS) in mouse astrocytes. Pretreatment of mouse astrocytes with either a ROS scavenger or an NAD(P)H oxidase inhibitor blocked bradykinin-induced activation of VSOR, glutamate release and astrocyte-to-neuron signalling. By contrast, pretreatment with BAPTA-AM or tetanus neurotoxin A failed to suppress bradykinin-induced glutamate release. Thus, VSOR activated by ROS in mouse astrocytes in response to stimulation with bradykinin, serves as the pathway for glutamate release to mediate astrocyte-to-neuron signalling. Since bradykinin is an initial mediator of inflammation, VSOR might play a role in glia-neuron communication in the brain during inflammation.