Rivera C, Voipio J, Payne J A, Ruusuvuori E, Lahtinen H, Lamsa K, Pirvola U, Saarma M, Kaila K
Department of Biosciences, University of Helsinki, Finland.
Nature. 1999 Jan 21;397(6716):251-5. doi: 10.1038/16697.
GABA (gamma-aminobutyric acid) is the main inhibitory transmitter in the adult brain, and it exerts its fast hyperpolarizing effect through activation of anion (predominantly Cl-)-permeant GABA(A) receptors. However, during early neuronal development, GABA(A)-receptor-mediated responses are often depolarizing, which may be a key factor in the control of several Ca2+-dependent developmental phenomena, including neuronal proliferation, migration and targeting. To date, however, the molecular mechanism underlying this shift in neuronal electrophysiological phenotype is unknown. Here we show that, in pyramidal neurons of the rat hippocampus, the ontogenetic change in GABA(A)-mediated responses from depolarizing to hyperpolarizing is coupled to a developmental induction of the expression of the neuronal (Cl-)-extruding K+/Cl- co-transporter, KCC2. Antisense oligonucleotide inhibition of KCC2 expression produces a marked positive shift in the reversal potential of GABAA responses in functionally mature hippocampal pyramidal neurons. These data support the conclusion that KCC2 is the main Cl- extruder to promote fast hyperpolarizing postsynaptic inhibition in the brain.
γ-氨基丁酸（GABA）是成人大脑中主要的抑制性神经递质，它通过激活阴离子（主要是Cl-）通透的GABA（A）受体发挥快速超极化作用。然而，在神经元发育早期，GABA（A）受体介导的反应通常是去极化的，这可能是控制几种依赖Ca2+的发育现象（包括神经元增殖、迁移和靶向）的关键因素。然而，迄今为止，神经元电生理表型这种转变的分子机制尚不清楚。在这里，我们表明，在大鼠海马体的锥体神经元中，GABA（A）介导的反应从去极化到超极化的个体发育变化与神经元（Cl-）外向转运体K+/Cl-协同转运蛋白KCC2表达的发育诱导相关。反义寡核苷酸抑制KCC2表达会使功能成熟的海马体锥体神经元中GABAA反应的反转电位发生明显正向偏移。这些数据支持以下结论：KCC2是促进大脑中快速超极化突触后抑制的主要Cl-外向转运体。
