mGluR3 Activation Recruits Cytoplasmic TWIK-1 Channels to Membrane that Enhances Ammonium Uptake in Hippocampal Astrocytes

详细信息    查看全文

• 作者：Wei Wang ; Conrad M. Kiyoshi ; Yixing Du ; Baofeng Ma…
• 关键词：Astrocytes ; TWIK ; 1 channel ; Metabotropic glutamate receptor 3 ; Ammonium ; Endosomal trafficking ; Hippocampus
• 刊名：Molecular Neurobiology
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：53
• 期：9
• 页码：6169-6182
• 全文大小：2,624 KB
• 刊物主题：Neurosciences; Neurobiology; Cell Biology; Neurology;
• 出版者：Springer US
• ISSN：1559-1182
• 卷排序：53

文摘

TWIK-1 two-pore domain K+ channels are highly expressed in mature hippocampal astrocytes. While the TWIK-1 activity is readily detectable on astrocyte membrane, the majority of channels are retained in the intracellular compartments, which raises an intriguing question of whether the membrane TWIK-1 channels could be dynamically regulated for functions yet unknown. Here, the regulation of TWIK-1 membrane expression by G_i/G_o-coupled metabotropic glutamate receptor 3 (mGluR3) and its functional impact on ammonium uptake has been studied. Activation of mGluR3 induced a marked translocation of TWIK-1 channels from the cytoplasm to the membrane surface. Consistent with our early observation that membrane TWIK-1 behaves as nonselective monovalent cation channel, mGluR3-mediated TWIK-1 membrane expression was associated with a depolarizing membrane potential (V_M). As TWIK-1 exhibits a discernibly high permeability to ammonium (NH₄+), a critical substrate in glutamate-glutamine cycle for neurotransmitter replenishment, regulation of NH₄+ uptake capacity by TWIK-1 membrane expression was determined by response of astrocyte V_M to bath application of 5 mM NH₄Cl. Stimulation of mGluR3 potentiated NH₄+-induced V_M depolarization by ∼30 % in wild type, but not in TWIK-1 knockout astrocytes. Furthermore, activation of mGluR3 mediated a coordinated translocation of TWIK-1 channels with recycling endosomes toward astrocyte membrane and the mGluR3-mediated potentiation of NH₄+ uptake required a functional Rab-mediated trafficking pathway. Altogether, we demonstrate that the activation of mGluR3 up-regulates the membrane expression of TWIK-1 that in turn enhances NH₄+ uptake in astrocytes, a mechanism potentially important for functional coupling of astrocyte glutamate-glutamine cycle with the replenishment of neurotransmitters in neurons.