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The Journal of Neuroscience, July 1, 2009, 29(26):8551-8564; doi:10.1523/JNEUROSCI.5784-08.2009

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Cellular/Molecular
TWIK-1 and TREK-1 Are Potassium Channels Contributing Significantly to Astrocyte Passive Conductance in Rat Hippocampal Slices

Min Zhou,¹ Guangjin Xu,³ Minjie Xie,³ Xuexin Zhang,² Gary P. Schools,¹ Liqun Ma,² Harold K. Kimelberg,¹ and Haijun Chen²

¹Ordway Research Institute, Albany, New York 12208, ²Department of Biological Sciences, University at Albany, State University of New York, Albany, New York 12222, and ³Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China

Correspondence should be addressed to either of the following: Dr. Min Zhou, Ordway Research Institute, 150 New Scotland Avenue, Albany, NY 12208, Email: mzhou{at}ordwayresearch.org; or Dr. Haijun Chen, Department of Biological Sciences, University at Albany, State University of New York, Albany, NY 12222, Email: hc323616{at}albany.edu

Expression of a linear current–voltage (I–V) relationship (passive) K⁺ membrane conductance is a hallmark of mature hippocampal astrocytes. However, the molecular identifications of the K⁺ channels underlying this passive conductance remain unknown. We provide the following evidence supporting significant contribution of the two-pore domain K⁺ channel (K_2P) isoforms, TWIK-1 and TREK-1, to this conductance. First, both passive astrocytes and the cloned rat TWIK-1 and TREK-1 channels expressed in CHO cells conduct significant amounts of Cs⁺ currents, but vary in their relative P_Cs/P_K permeability, 0.43, 0.10, and 0.05, respectively. Second, quinine, which potently inhibited TWIK-1 (IC₅₀ = 85 µM) and TREK-1 (IC₅₀ = 41 µM) currents, also inhibited astrocytic passive conductance by 58% at a concentration of 200 µM. Third, a moderate sensitivity of passive conductance to low extracellular pH (6.0) supports a combined expression of acid-insensitive TREK-1, and to a lesser extent, acid-sensitive TWIK-1. Fourth, the astrocyte passive conductance showed low sensitivity to extracellular Ba²⁺, and extracellular Ba²⁺ blocked TWIK-1 channels at an IC₅₀ of 960 µM and had no effect on TREK-1 channels. Finally, an immunocytochemical study showed colocalization of TWIK-1 and TREK-1 proteins with the astrocytic markers GLAST and GFAP in rat hippocampal stratum radiatum. In contrast, another K_2P isoform TASK-1 was mainly colocalized with the neuronal marker NeuN in hippocampal pyramidal neurons and was expressed at a much lower level in astrocytes. These results support TWIK-1 and TREK-1 as being the major components of the long-sought K⁺ channels underlying the passive conductance of mature hippocampal astrocytes.

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Received Dec. 3, 2008; revised May 4, 2009; accepted June 3, 2009.

Correspondence should be addressed to either of the following: Dr. Min Zhou, Ordway Research Institute, 150 New Scotland Avenue, Albany, NY 12208, Email: mzhou{at}ordwayresearch.org; or Dr. Haijun Chen, Department of Biological Sciences, University at Albany, State University of New York, Albany, NY 12222, Email: hc323616{at}albany.edu

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