Journal
MOLECULAR NEUROBIOLOGY
Volume 53, Issue 9, Pages 6169-6182Publisher
HUMANA PRESS INC
DOI: 10.1007/s12035-015-9496-4
Keywords
Astrocytes; TWIK-1 channel; Metabotropic glutamate receptor 3; Ammonium; Endosomal trafficking; Hippocampus
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Funding
- National Institute of Neurological Disorders and Stroke [RO1NS062784]
- Ohio State University College of Medicine
- National Natural Science Foundation of China [81400973]
- Fundamental Research Funds for the Central Universities of China, HUST [2015QN146]
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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 similar to 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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