Mislocalization of Kir channels in malignant glia

✍ Scribed by M.L. Olsen; H. Sontheimer

• Publisher: John Wiley and Sons
• Year: 2004
• Tongue: English
• Weight: 497 KB
• Volume: 46
• Category: Article
• ISSN: 0894-1491
• DOI: 10.1002/glia.10346

✦ Synopsis

Abstract

Inwardly rectifying potassium (K~ir~) channels are a prominent feature of mature, postmitotic astrocytes. These channels are believed to set the resting membrane potential near the potassium equilibrium potential (E~K~) and are implicated in potassium buffering. A number of previous studies suggest that K~ir~ channel expression is indicative of cell differentiation. We therefore set out to examine K~ir~ channel expression in malignant glia, which are incapable of differentiation. We used two established and widely used glioma cell lines, D54MG (a WHO grade 4 glioma) and STTG‐1 (a WHO grade 3 glioma), and compared them to immature and differentiated astrocytes. Both glioma cell lines were characterized by large outward K^+^ currents, depolarized resting membrane potentials (V~m~) (−38.5 ± 4.2 mV, D54 and −28.1 ± 3.5 mV, STTG1), and relatively high input resistances (R~m~) (260.6 ± 64.7 MΩ, D54 and 687.2 ± 160.3 MΩ, STTG1). These features were reminiscent of immature astrocytes, which also displayed large outward K^+^ currents, had a mean V~m~ of −51.1 ± 3.7 and a mean R~m~ value of 627.5 ± 164 MΩ. In contrast, mature astrocytes had a significantly more negative resting membrane potential (−75.2 ± 0.56 mV), and a mean R~m~ of 25.4 ± 7.4 MΩ. Barium (Ba^2+^) sensitive K~ir~ currents were >20‐fold larger in mature astrocytes (4.06 ± 1.1 nS/pF) than in glioma cells (0.169 ± 0.033 nS/pF D54, 0.244 ± 0.04 nS/pF STTG1), which had current densities closer to those of dividing, immature astrocytes (0.474 ± 0.12 nS/pF). Surprisingly, Western blot analysis shows expression of several K~ir~ channel subunits in glioma cells (K~ir~2.3, 3.1, and 4.1). However, while in astrocytes these channels localize diffusely throughout the cell, in glioma cells they are found almost exclusively in either the cell nucleus (K~ir~2.3 and 4.1) or ER/Golgi (3.1). These data suggest that mislocalization of K~ir~ channel proteins to intracellular compartments is responsible for a lack of appreciable K~ir~ currents in glioma cells. © 2004 Wiley‐Liss, Inc.