Microglial Ramification, Surveillance, and Interleukin-1β Release Are Regulated by the Two-Pore Domain K(+) Channel THIK-1.
Microglial Ramification, Surveillance, and Interleukin-1β Release Are Regulated by the Two-Pore Domain K(+) Channel THIK-1.
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小胶质分支，监视和白介素-1β释放受两孔域K（+）通道Thik-1的调节。
DOI：
10.1016/j.neuron.2017.12.002
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发表时间：
2018-01-17
期刊：
影响因子：
16.2
通讯作者：
Attwell D
中科院分区：
文献类型：
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作者：
Madry C;Kyrargyri V;Arancibia-Cárcamo IL;Jolivet R;Kohsaka S;Bryan RM;Attwell D
小胶质细胞表现出两种运动模式：它们不断地伸展和收缩它们的过程来调查大脑，但它们也发出有针对性的过程来包裹组织损伤的部位。我们现在表明，这些运动模式不同的机制。我们确定了两个孔域通道THIK-1作为主要的K+通道在小胶质细胞原位表达。THIK-1具有紧张性活性，其活性通过P2 Y12受体增强。通过基因敲除抑制THIK-1功能可使小胶质细胞去极化，从而减少小胶质细胞分支，从而减少监视，而阻断P2 Y12受体不影响膜电位、分支或监视。相反，受损组织的过程生长需要P2 Y12受体激活，但不受THIK-1阻断的影响。THIK-1功能的阻断还抑制促炎细胞因子白细胞介素-1 β从活化的小胶质细胞的释放，这与炎性小体组装所需的K+损失一致。因此，小胶质细胞免疫监视和细胞因子释放需要THIK-1通道活性。THIK-1的紧张性活性维持小胶质细胞的静息电位阻断THIK-1可减少小胶质细胞的分支、监视和IL-1β的释放监视依赖于THIK-1，而不是P2 Y12;趋化性依赖于P2 Y12，而不是THIK-1小胶质细胞在发育过程中调查大脑中的入侵微生物，去除垂死的神经元并修剪突触。我们发现，THIK-1 K+通道维持小胶质细胞静息电位对于维持小胶质细胞分支、监视和白细胞介素-1 β释放至关重要。
Microglia exhibit two modes of motility: they constantly extend and retract their processes to survey the brain, but they also send out targeted processes to envelop sites of tissue damage. We now show that these motility modes differ mechanistically. We identify the two-pore domain channel THIK-1 as the main K+ channel expressed in microglia in situ. THIK-1 is tonically active, and its activity is potentiated by P2Y12 receptors. Inhibiting THIK-1 function pharmacologically or by gene knockout depolarizes microglia, which decreases microglial ramification and thus reduces surveillance, whereas blocking P2Y12 receptors does not affect membrane potential, ramification, or surveillance. In contrast, process outgrowth to damaged tissue requires P2Y12 receptor activation but is unaffected by blocking THIK-1. Block of THIK-1 function also inhibits release of the pro-inflammatory cytokine interleukin-1β from activated microglia, consistent with K+ loss being needed for inflammasome assembly. Thus, microglial immune surveillance and cytokine release require THIK-1 channel activity. The two-pore domain channel THIK-1 is the main K+ channel in “resting” microglia Tonic activity of THIK-1 maintains the microglial resting potential Blocking THIK-1 reduces microglial ramification, surveillance, and IL-1β release Surveillance depends on THIK-1, not P2Y12; chemotaxis depends on P2Y12, not THIK-1 Microglia survey the brain for invading micro-organisms, remove dying neurons, and prune synapses during development. We show that maintenance of the microglial resting potential by THIK-1 K+ channels is essential for maintaining microglial ramification, surveillance, and interleukin-1β release.
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影响因子：
3.7
作者：
Hines DJ;Choi HB;Hines RM;Phillips AG;MacVicar BA
通讯作者：
MacVicar BA
DOI：
10.1007/978-1-60327-019-9_8
发表时间：
2009-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Gardiner, Wendy J K;Teboul, Lydia
通讯作者：
Teboul, Lydia
影响因子：
3.7
作者：
Charolidi N;Schilling T;Eder C
通讯作者：
Eder C
影响因子：
7.1
作者：
Holtman IR;Raj DD;Miller JA;Schaafsma W;Yin Z;Brouwer N;Wes PD;Möller T;Orre M;Kamphuis W;Hol EM;Boddeke EW;Eggen BJ
通讯作者：
Eggen BJ
影响因子：
16.6
作者：
通讯作者：
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