Santos Hélio R, Ribeiro Helizane S, Setti-Perdigão Pedro, Albuquerque Edson X, Castro Newton G
Departmento de Farmacologia Básica e Clínica, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde, Rio de Janeiro, Brazil.
J Pharmacol Exp Ther. 2006 Oct;319(1):376-85. doi: 10.1124/jpet.106.106385. Epub 2006 Jul 12.
Hippocampal alpha7() nicotinic acetylcholine receptors modulate the release of GABA and glutamate. The control of functional receptor pools by cell firing or synaptic activity could therefore allow for a local adjustment of the sensitivity to cholinergic input upon changes in neuronal activity. We first investigated whether tonic depolarization or cell firing affected the function of alpha7(). The amplitude of alpha7()-gated whole-cell currents in cultured rat hippocampal neurons exposed to high-extracellular K(+) (40 mM KCl) for 24 to 48 h increased 1.3 to 5.5 times. The proportion of alpha7()-responsive neurons (99%), the potency of acetylcholine, and the sensitivity to nicotinic antagonists were all unaffected. In contrast, block of spontaneous cell firing with tetrodotoxin for 24 h led to a 37% reduction in mean current amplitude. Reduced alpha7() responses were seen after a 24-h blockade of N-type calcium channels but not of L-type calcium channels, N-methyl-d-aspartate (NMDA), or non-NMDA receptor channels, protein kinase C, or calcium-calmodulin kinases II and IV. The N-type or L-type calcium channel antagonists omega-conotoxin GVIA and nifedipine did not prevent the current-potentiating effect of KCl. The GABA(A) antagonist picrotoxin led to a 44% reduction of the currents, despite increasing action potential firing, and also reversed the potentiating effect of KCl. Treatment with GABA, midazolam, or a GABA uptake blocker led to increased currents. These data indicate that alpha7()-gated currents in hippocampal neurons are regulated by GABAergic activity and suggest that depolarization-induced GABA release may underlie the effect of increased extracellular KCl.
海马体α7（）烟碱型乙酰胆碱受体调节γ-氨基丁酸（GABA）和谷氨酸的释放。因此，通过细胞放电或突触活动对功能性受体库的控制，可能允许在神经元活动发生变化时对胆碱能输入的敏感性进行局部调节。我们首先研究了强直性去极化或细胞放电是否会影响α7（）的功能。在高细胞外钾（40 mM氯化钾）中暴露24至48小时的培养大鼠海马神经元中，α7（）门控全细胞电流的幅度增加了1.3至5.5倍。α7（）反应性神经元的比例（99%）、乙酰胆碱的效力以及对烟碱拮抗剂的敏感性均未受影响。相比之下，用河豚毒素阻断自发细胞放电24小时导致平均电流幅度降低37%。在N型钙通道被阻断24小时后，α7（）反应降低，但L型钙通道、N-甲基-D-天冬氨酸（NMDA）或非NMDA受体通道、蛋白激酶C或钙调蛋白激酶II和IV被阻断后则未出现这种情况。N型或L型钙通道拮抗剂ω-芋螺毒素GVIA和硝苯地平并未阻止氯化钾的电流增强作用。尽管动作电位发放增加，但GABA（A）拮抗剂荷包牡丹碱使电流降低了44%，并且还逆转了氯化钾的增强作用。用GABA、咪达唑仑或GABA摄取阻滞剂处理导致电流增加。这些数据表明，海马神经元中α7（）门控电流受GABA能活动调节，并表明去极化诱导的GABA释放可能是细胞外氯化钾增加效应的基础。
