NDLI: MGluR3 Activation Recruits Cytoplasmic TWIK-1 Channels to Membrane that Enhances Ammonium Uptake in Hippocampal Astrocytes

Content Provider	Springer Nature Link
Author	Wang, Wei Kiyoshi, Conrad M. Du, Yixing Ma, Baofeng Alford, Catherine C. Chen, Haijun Zhou, Min
Copyright Year	2015
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 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 (NH$_{4}$ $^{+}$), a critical substrate in glutamate-glutamine cycle for neurotransmitter replenishment, regulation of NH$_{4}$ $^{+}$ uptake capacity by TWIK-1 membrane expression was determined by response of astrocyte V $_{M}$ to bath application of 5 mM NH$_{4}$Cl. Stimulation of mGluR3 potentiated NH$_{4}$ $^{+}$-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 NH$_{4}$ $^{+}$ 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 NH$_{4}$ $^{+}$ uptake in astrocytes, a mechanism potentially important for functional coupling of astrocyte glutamate-glutamine cycle with the replenishment of neurotransmitters in neurons.
Starting Page	6169
Ending Page	6182
Page Count	14
File Format	PDF
ISSN	08937648
Journal	Molecular Neurobiology
Volume Number	53
Issue Number	9
e-ISSN	15591182
Language	English
Publisher	Springer US
Publisher Date	2015-11-10
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Astrocytes TWIK-1 channel Metabotropic glutamate receptor 3 Ammonium Endosomal trafficking Hippocampus Neurosciences Neurobiology Cell Biology Neurology
Content Type	Text
Resource Type	Article
Subject	Neurology Cellular and Molecular Neuroscience

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