Brody D L, Yue D T
The Johns Hopkins University School of Medicine, Departments of Biomedical Engineering and Neuroscience, Program in Molecular and Cellular Systems Physiology, Baltimore, Maryland 21205, USA.
J Neurosci. 2000 Feb 1;20(3):889-98. doi: 10.1523/JNEUROSCI.20-03-00889.2000.
G-protein inhibition of voltage-gated calcium channels can be transiently relieved by repetitive physiological stimuli. Here, we provide evidence that such relief of inhibition contributes to short-term synaptic plasticity in microisland-cultured hippocampal neurons. With G-protein inhibition induced by the GABA(B) receptor agonist baclofen or the adenosine A1 receptor agonist 2-chloroadenosine, short-term synaptic facilitation emerged during action potential trains. The facilitation decayed with a time constant of approximately 100 msec. However, addition of the calcium channel inhibitor Cd(2+) at 2-3 microM had no such effect and did not alter baseline synaptic depression. As expected of facilitation from relief of channel inhibition, analysis of miniature EPSCs implicated presynaptic modulation, and elevating presynaptic Ca(2+) entry blunted the facilitation. Most telling was the near occlusion of synaptic facilitation after selective blockade of P/Q- but not N-type calcium channels. This was as predicted from experiments using recombinant calcium channels expressed in human embryonic kidney (HEK) 293 cells; we found significantly stronger relief of G-protein inhibition in recombinant P/Q- versus N-type channels during action potential trains. G-protein inhibition in HEK 293 cells was induced via recombinant M2 muscarinic acetylcholine receptors activated by carbachol, an acetylcholine analog. Thus, relief of G-protein inhibition appears to produce a novel form of short-term synaptic facilitation in cultured neurons. Similar short-term synaptic plasticity may be present at a wide variety of synapses, as it could occur during autoreceptor inhibition by glutamate or GABA, heterosynaptic inhibition by GABA, tonic adenosine inhibition, and in many other instances.
G蛋白对电压门控钙通道的抑制作用可被重复性生理刺激短暂解除。在此，我们提供证据表明这种抑制的解除有助于微岛培养的海马神经元的短期突触可塑性。在由GABA(B)受体激动剂巴氯芬或腺苷A1受体激动剂2-氯腺苷诱导的G蛋白抑制作用下，动作电位串期间出现了短期突触易化。这种易化以约100毫秒的时间常数衰减。然而，添加2-3微摩尔的钙通道抑制剂Cd(2+)没有这种作用，也没有改变基线突触抑制。正如通道抑制解除所预期的易化那样，微小兴奋性突触后电流的分析表明是突触前调制，并且提高突触前Ca(2+)内流会减弱这种易化。最能说明问题的是，选择性阻断P/Q型而非N型钙通道后，突触易化几乎完全被阻断。这与使用在人胚肾(HEK) 293细胞中表达的重组钙通道进行的实验预测一致；我们发现在动作电位串期间，重组P/Q型通道中G蛋白抑制的解除比N型通道明显更强。HEK 293细胞中的G蛋白抑制是通过乙酰胆碱类似物卡巴胆碱激活的重组M2毒蕈碱型乙酰胆碱受体诱导的。因此，G蛋白抑制的解除似乎在培养的神经元中产生了一种新型的短期突触易化。类似的短期突触可塑性可能存在于多种突触中，因为它可能发生在谷氨酸或GABA的自身受体抑制、GABA的异突触抑制、持续性腺苷抑制以及许多其他情况下。
