Chen G, van den Pol A N
Department of Neurosurgery, Yale University Medical School, New Haven, Connecticut 06520, USA.
J Neurosci. 1998 Mar 1;18(5):1913-22. doi: 10.1523/JNEUROSCI.18-05-01913.1998.
GABA is the primary transmitter released by neurons of the suprachiasmatic nucleus (SCN), the circadian clock in the brain. Whereas GABAB receptor agonists exert a significant effect on circadian rhythms, the underlying mechanism by which GABAB receptors act in the SCN has remained a mystery. We found no GABAB receptor-mediated effect on slow potassium conductance, membrane potential, or input resistance in SCN neurons in vitro using whole-cell patch-clamp recording. In contrast, the GABAB receptor agonist baclofen (1-100 microM) exerted a large and dose-dependent inhibition (up to 100%) of evoked IPSCs. Baclofen reduced the frequency of spontaneous IPSCs but showed little effect on the frequency or amplitude of miniature IPSCs in the presence of tetrodotoxin. The activation of GABAB receptors did not modulate postsynaptic GABAA receptor responses. The depression of GABA release by GABAB autoreceptors appeared to be mediated primarily through a modulation of presynaptic calcium channels. The baclofen inhibition of both calcium currents and evoked IPSCs was greatly reduced (up to 100%) by the P/Q-type calcium channel blocker agatoxin IVB, suggesting that P/Q-type calcium channels are the major targets involved in the modulation of GABA release. To a lesser degree, N-type calcium channels were also involved. The inhibition of GABA release by baclofen was abolished by a pretreatment with pertussis toxin (PTX), whereas the inhibition of whole-cell calcium currents by baclofen was only partially depressed by PTX, suggesting that G-protein mechanisms involved in GABAB receptor modulation at the soma and axon terminal may not be identical. We conclude that GABAB receptor activation exerts a strong presynaptic inhibition of GABA release in SCN neurons, primarily by modulating P/Q-type calcium channels at axon terminals.
γ-氨基丁酸（GABA）是视交叉上核（SCN）神经元释放的主要神经递质，而视交叉上核是大脑中的昼夜节律时钟。虽然GABAB受体激动剂对昼夜节律有显著影响，但GABAB受体在视交叉上核中发挥作用的潜在机制仍是个谜。我们使用全细胞膜片钳记录法在体外未发现GABAB受体对视交叉上核神经元的慢钾电导、膜电位或输入电阻有介导作用。相反，GABAB受体激动剂巴氯芬（1 - 100微摩尔）对诱发的抑制性突触后电流（IPSCs）产生了强烈且剂量依赖性的抑制作用（高达100%）。巴氯芬降低了自发性IPSCs的频率，但在存在河豚毒素的情况下，对微小IPSCs的频率或幅度影响很小。GABAB受体的激活并未调节突触后GABAA受体反应。GABAB自身受体对GABA释放的抑制作用似乎主要是通过对突触前钙通道的调节来介导的。P/Q型钙通道阻滞剂阿加毒素IVB可使巴氯芬对钙电流和诱发的IPSCs的抑制作用大大降低（高达100%），这表明P/Q型钙通道是参与调节GABA释放的主要靶点。在较小程度上，N型钙通道也参与其中。用百日咳毒素（PTX）预处理可消除巴氯芬对GABA释放的抑制作用，而巴氯芬对全细胞钙电流的抑制作用仅被PTX部分抑制，这表明在胞体和轴突末端参与GABAB受体调节的G蛋白机制可能并不相同。我们得出结论，GABAB受体激活对视交叉上核神经元的GABA释放产生强烈的突触前抑制作用，主要是通过调节轴突末端的P/Q型钙通道来实现的。
