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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Acknowledgments
This work is sponsored by grants from the National Institute of Neurological Disorders and Stroke RO1NS062784 (MZ), start-up fund from the Ohio State University College of Medicine (MZ), the National Natural Science Foundation of China (No. 81400973) (WW), and the Fundamental Research Funds for the Central Universities of China, HUST (2015QN146) (WW).
Authors’ contributions
WW and MZ conceived the project. WW, CMK, YD, BM, CCA, and HC conducted the research or assisted the research, discussed the project, and assisted the manuscript preparation. WW and MZ wrote the manuscript. MZ supervised the project.
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Wang, W., Kiyoshi, C.M., Du, Y. et al. mGluR3 Activation Recruits Cytoplasmic TWIK-1 Channels to Membrane that Enhances Ammonium Uptake in Hippocampal Astrocytes. Mol Neurobiol 53, 6169–6182 (2016). https://doi.org/10.1007/s12035-015-9496-4
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DOI: https://doi.org/10.1007/s12035-015-9496-4