Mulholland Patrick J, Carpenter-Hyland Ezekiel P, Hearing Matthew C, Becker Howard C, Woodward John J, Chandler L Judson
Department of Neurosciences and Center for Drug and Alcohol Programs, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
J Neurosci. 2008 Aug 27;28(35):8801-9. doi: 10.1523/JNEUROSCI.2405-08.2008.
Delayed-rectifier Kv2.1 potassium channels regulate somatodendritic excitability during periods of repetitive, high-frequency activity. Recent evidence suggests that Kv2.1 channel modulation is linked to glutamatergic neurotransmission. Because NMDA-type glutamate receptors are critical regulators of synaptic plasticity, we investigated NMDA receptor modulation of Kv2.1 channels in rodent hippocampus and cortex. Bath application of NMDA potently unclustered and dephosphorylated Kv2.1 and produced a hyperpolarizing shift in voltage-dependent activation of voltage-sensitive potassium currents (I(K)). In contrast, driving synaptic activity in Mg2+-free media to hyperactivate synaptic NMDA receptors had no effect on Kv2.1 channels, and moderate pentylenetetrazole-induced seizure activity in adult mice did not dephosphorylate hippocampal Kv2.1 channels. Selective activation of extrasynaptic NMDA receptors unclustered and dephosphorylated Kv2.1 channels and produced a hyperpolarizing shift in neuronal I(K). In addition, inhibition of glutamate uptake rapidly activated NMDA receptors and dephosphorylated Kv2.1 channels. These observations demonstrate that regulation of intrinsic neuronal activity by Kv2.1 is coupled to extrasynaptic but not synaptic NMDA receptors. These data support a novel mechanism for glutamate transporters in regulation of neuronal excitability and plasticity through extrasynaptic NMDA receptor modulation of Kv2.1 channels.
延迟整流型Kv2.1钾通道在重复性高频活动期间调节树突棘兴奋性。最近的证据表明,Kv2.1通道调节与谷氨酸能神经传递有关。由于NMDA型谷氨酸受体是突触可塑性的关键调节因子,我们研究了啮齿动物海马体和皮质中Kv2.1通道的NMDA受体调节作用。浴槽应用NMDA可有效使Kv2.1去簇集并使其去磷酸化,并使电压敏感性钾电流(I(K))的电压依赖性激活产生超极化偏移。相比之下,在无镁培养基中驱动突触活动以超激活突触NMDA受体对Kv2.1通道没有影响,并且成年小鼠中适度的戊四氮诱导的癫痫活动并未使海马体Kv2.1通道去磷酸化。突触外NMDA受体的选择性激活使Kv2.1通道去簇集并使其去磷酸化,并使神经元I(K)产生超极化偏移。此外,抑制谷氨酸摄取可迅速激活NMDA受体并使Kv2.1通道去磷酸化。这些观察结果表明,Kv2.1对内在神经元活动的调节与突触外而非突触NMDA受体相关。这些数据支持了谷氨酸转运体通过突触外NMDA受体对Kv2.1通道的调节来调控神经元兴奋性和可塑性的新机制。