Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110.
Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110.
eNeuro. 2017 Jun 23;4(3). doi: 10.1523/ENEURO.0114-17.2017. eCollection 2017 May-Jun.
The GABA-B receptor is densely expressed throughout the brain and has been implicated in many CNS functions and disorders, including addiction, epilepsy, spasticity, schizophrenia, anxiety, cognitive deficits, and depression, as well as various aspects of nervous system development. How one GABA-B receptor is involved in so many aspects of CNS function remains unanswered. Activation of GABA-B receptors is normally thought to produce inhibitory responses in the nervous system, but puzzling contradictory responses exist. Here we report that in rat mitral cells of the olfactory bulb, GABA-B receptor activation inhibits both the persistent sodium current (INa) and the sodium-activated potassium current (IK), which is coupled to it. We find that the primary effect of GABA-B activation is to inhibit INa, which has the secondary effect of inhibiting IK because of its dependence on persistent sodium entry for activation. This can have either a net excitatory or inhibitory effect depending on the balance of INa/IK currents in neurons. In the olfactory bulb, the cell bodies of mitral cells are densely packed with sodium-activated potassium channels. These channels produce a large IK which, if constitutively active, would shunt any synaptic potentials traversing the soma before reaching the spike initiation zone. However, GABA-B receptor activation might have the net effect of reducing the IK blocking effect, thus enhancing the effectiveness of synaptic potentials.
GABA-B 受体在大脑中广泛表达，并与许多中枢神经系统功能和疾病有关，包括成瘾、癫痫、痉挛、精神分裂症、焦虑、认知缺陷和抑郁，以及神经系统发育的各个方面。一个 GABA-B 受体如何参与中枢神经系统功能的如此多方面仍然没有答案。GABA-B 受体的激活通常被认为会在神经系统中产生抑制反应，但存在令人费解的矛盾反应。在这里，我们报告在大鼠嗅球的僧帽细胞中，GABA-B 受体的激活抑制了持续钠电流 (INa) 和与之偶联的钠激活钾电流 (IK)。我们发现 GABA-B 激活的主要作用是抑制 INa，由于其对持续钠内流的激活依赖性，这具有抑制 IK 的次要作用。这可能根据神经元中 INa/IK 电流的平衡产生净兴奋或抑制作用。在嗅球中，僧帽细胞的胞体密集排列着钠激活钾通道。这些通道产生的大 IK，如果持续激活，会在到达起始区之前对穿过胞体的任何突触电位进行分流。然而，GABA-B 受体的激活可能会产生降低 IK 阻断作用的净效果，从而增强突触电位的有效性。
