Mind the translational gap: human microglia differ from mouse microglia in their regulation of Kv and Kir2.1 channels

Schilling, S.; Felk, J.; Kikhia, M.; Podesta, A.; Hintze, J.; Fidzinski, P.; Holtkamp, M.; Onken, J.; Sauvigny, T.; Kalbhenn, T.; Simon, M.; Kettenmann, H.; Endres, M.; Goettert, R.; Gertz, K.

doi:10.64898/2026.03.10.710589

bioRxiv · 10.64898/2026.03.10.710589

Mind the translational gap: human microglia differ from mouse microglia in their regulation of Kv and Kir2.1 channels

Schilling, S.·Felk, J.·Kikhia, M.·Podesta, A.·Hintze, J.·Fidzinski, P.·Holtkamp, M.·Onken, J.·Sauvigny, T.·Kalbhenn, T.·Simon, M.·Kettenmann, H.·Endres, M.·Goettert, R.·Gertz, K.

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Abstract

K+ channels are important for controlling membrane potential and regulating functional properties of microglia. Whereas the inward-rectifying K+ (Kir) channel 2.1 modulates proliferation, voltage-gated K+ channels (Kv) are linked to inflammatory response in mouse microglia (mMG). These channels serve as possible drug targets but little is known regarding their activity in human microglia. We used patch-clamp recording to study membrane currents of primary human microglia (hMG) and human induced pluripotent stem cell-derived microglia-like cells (hiPSC-MGL) and compared them with mMG. Unlike mMG, hMG and hiPSC-MGL exhibited Kir2.1 currents only after LPS+IFN-{gamma} stimulation. Interestingly, Kv currents were not observed in hMG or hiPSC-MGL under any condition. While mMG had a progressively ameboid morphology after stimulation, hMG showed few morphological changes and hiPSC-MGL increased ramification. Overall, the activity of Kir2.1 and Kv channels in hMG and hiPSC-MGL differs fundamentally from mMG. Our findings highlight differences between species and underscore the need for translational approaches.

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Schilling, S., Felk, J., Kikhia, M., Podesta, A., Hintze, J., Fidzinski, P., Holtkamp, M., Onken, J., Sauvigny, T., Kalbhenn, T., Simon, M., Kettenmann, H., Endres, M., Goettert, R., Gertz, K.. 2026-03-10. Mind the translational gap: human microglia differ from mouse microglia in their regulation of Kv and Kir2.1 channels. https://doi.org/10.64898/2026.03.10.710589

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