Tzingounis Anastassios V, Heidenreich Matthias, Kharkovets Tatjana, Spitzmaul Guillermo, Jensen Henrik S, Nicoll Roger A, Jentsch Thomas J
Department of Cellular and Molecular Pharmacology and Department of Physiology, University of California, San Francisco, CA 94143, USA.
Proc Natl Acad Sci U S A. 2010 Jun 1;107(22):10232-7. doi: 10.1073/pnas.1004644107. Epub 2010 May 13.
Mutations in KCNQ2 and KCNQ3 voltage-gated potassium channels lead to neonatal epilepsy as a consequence of their key role in regulating neuronal excitability. Previous studies in the brain have focused primarily on these KCNQ family members, which contribute to M-currents and afterhyperpolarization conductances in multiple brain areas. In contrast, the function of KCNQ5 (Kv7.5), which also displays widespread expression in the brain, is entirely unknown. Here, we developed mice that carry a dominant negative mutation in the KCNQ5 pore to probe whether it has a similar function as other KCNQ channels. This mutation renders KCNQ5(dn)-containing homomeric and heteromeric channels nonfunctional. We find that Kcnq5(dn/dn) mice are viable and have normal brain morphology. Furthermore, expression and neuronal localization of KCNQ2 and KCNQ3 subunits are unchanged. However, in the CA3 area of hippocampus, a region that highly expresses KCNQ5 channels, the medium and slow afterhyperpolarization currents are significantly reduced. In contrast, neither current is affected in the CA1 area of the hippocampus, a region with low KCNQ5 expression. Our results demonstrate that KCNQ5 channels contribute to the afterhyperpolarization currents in hippocampus in a cell type-specific manner.
KCNQ2和KCNQ3电压门控钾通道的突变会导致新生儿癫痫，因为它们在调节神经元兴奋性方面起着关键作用。此前在大脑中的研究主要集中在这些KCNQ家族成员上，它们在多个脑区中对M电流和超极化后电导有贡献。相比之下，同样在大脑中广泛表达的KCNQ5（Kv7.5）的功能却完全未知。在这里，我们构建了在KCNQ5孔区携带显性负性突变的小鼠，以探究它是否具有与其他KCNQ通道类似的功能。这种突变使含有KCNQ5（dn）的同聚体和异聚体通道失去功能。我们发现Kcnq5（dn/dn）小鼠能够存活且脑形态正常。此外，KCNQ2和KCNQ3亚基的表达及神经元定位没有变化。然而，在高度表达KCNQ5通道的海马体CA3区，中等和慢速超极化后电流显著降低。相比之下，在KCNQ5表达较低的海马体CA1区，这两种电流均未受影响。我们的结果表明，KCNQ5通道以细胞类型特异性的方式对海马体中的超极化后电流有贡献。
