Disrupted Cl(-) homeostasis contributes to reductions in the inhibitory efficacy of diazepam during hyperexcited states.
Disrupted Cl(-) homeostasis contributes to reductions in the inhibitory efficacy of diazepam during hyperexcited states.
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DOI：
10.1111/ejn.12241
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发表时间：
2013-08
期刊：
影响因子：
--
通讯作者：
Moss SJ
中科院分区：
文献类型：
--
作者：
Deeb TZ;Nakamura Y;Frost GD;Davies PA;Moss SJ
K+-Cl-协同转运蛋白KCC 2是大多数成年神经元中主要的Cl-排出机制。这一过程反过来导致GABAA受体激活时Cl−内流和典型的超极化抑制性突触后电位。几种神经系统疾病的治疗药物，目标和增强GABAA受体信号，包括常用的苯二氮卓类安定和麻醉剂丙泊酚。这些疾病中的一些也与GABAA信号传导的缺陷相关，并且对靶向GABAA受体的治疗药物变得不太敏感。迄今为止，尚不清楚神经元Cl−梯度的改变是否会影响地西泮和丙泊酚的疗效。因此，我们使用谷氨酸诱导的超兴奋性的体外模型来测试Cl−梯度的改变是否影响GABAA调节剂的功效。我们专门利用短杆菌肽穿孔膜片钳配置，以保持内源性Cl−梯度。短暂暴露于谷氨酸会在5分钟内降低地西泮的抑制效果，这是由于Cl−梯度的崩溃，而不是由于GABAA受体数量的减少。与地西泮不同，尽管谷氨酸诱导出现去极化GABA A介导的电流，丙泊酚仍通过分流膜电导保持其疗效。类似地，呋塞米对KCC 2的药理学抑制破坏了Cl−的体内平衡，降低了地西泮的疗效，但对丙泊酚没有影响。总的来说，我们的结果表明，病理性过度兴奋条件可能导致细胞内Cl−的快速积累和去极化GABA介导的电流的出现，这将降低地西泮的疗效。
The K+-Cl− cotransporter KCC2 is the major Cl− extrusion mechanism in most adult neurons. This process in turn leads to Cl− influx upon activation of GABAA receptors and the canonical hyperpolarizing inhibitory postsynaptic potential. Several neurological disorders are treated with drugs that target and enhance GABAA receptor signaling, including the commonly used benzodiazepine diazepam and the anesthetic propofol. Some of these disorders are also associated with deficits in GABAA signaling and become less sensitive to therapeutic drugs that target GABAA receptors. To date, it is unknown if alterations in the neuronal Cl− gradient affect the efficacies of diazepam and propofol. We therefore used the in vitro model of glutamate-induced hyperexcitability to test if alterations in the Cl− gradient affect the efficacy of GABAA modulators. We exclusively utilized the gramicidin perforated-patch clamp configuration to preserve the endogenous Cl− gradient. Brief exposure to glutamate reduced the inhibitory efficacy of diazepam within five minutes that was caused by the collapse of the Cl− gradient, and not due to reductions in GABAA receptor number. Unlike diazepam, propofol retained its efficacy by shunting the membrane conductance despite the glutamate-induced appearance of depolarizing GABAA-mediated currents. Similarly, pharmacological inhibition of KCC2 by furosemide disrupted Cl− homeostasis and reduced the efficacy of diazepam but not propofol. Collectively our results suggest pathological hyperexcitable conditions could cause the rapid accumulation of intracellular Cl− and the appearance of depolarizing GABAA-mediated currents that would decrease the efficacy of diazepam.
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影响因子：
4.3
作者：
Doyon N;Prescott SA;Castonguay A;Godin AG;Kröger H;De Koninck Y
通讯作者：
De Koninck Y
影响因子：
2.9
作者：
LALLEMENT, G;CARPENTIER, P;BLANCHET, G
通讯作者：
BLANCHET, G
影响因子：
8.3
作者：
Jaenisch, Nadine;Witte, Otto W.;Frahm, Christiane
通讯作者：
Frahm, Christiane
影响因子：
2.9
作者：
Kitamura, Akihiko;Ishibashi, Hitoshi;Nabekura, Junichi
通讯作者：
Nabekura, Junichi
影响因子：
3.6
作者：
Feng, HJ;Macdonald, RL
通讯作者：
Macdonald, RL