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

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          Abstract

          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 Gi/Go-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.

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          Author and article information

          Journal
          Mol. Neurobiol.
          Molecular neurobiology
          0893-7648
          0893-7648
          Nov 2016
          : 53
          : 9
          Affiliations
          [1 ] Department of Neuroscience, Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA. wwang@hust.edu.cn.
          [2 ] Department of Physiology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, China. wwang@hust.edu.cn.
          [3 ] Institute of Brain Research, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, China. wwang@hust.edu.cn.
          [4 ] Department of Neuroscience, Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA.
          [5 ] Department of Biological Sciences, University at Albany, State University of New York, Albany, NY, USA.
          [6 ] Department of Neuroscience, Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA. zhou.787@osu.edu.
          Article
          10.1007/s12035-015-9496-4 NIHMS736946
          10.1007/s12035-015-9496-4
          4862944
          26553349
          aa034c41-af2f-4f8c-973c-19a962f5982e
          History

          Ammonium,Astrocytes,Endosomal trafficking,Hippocampus,Metabotropic glutamate receptor 3,TWIK-1 channel

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