Desensitization-resistant and -sensitive GPCR-mediated inhibition of GABA release occurs by Ca2+-dependent and -independent mechanisms at a hypothalamic synapse.
Desensitization-resistant and -sensitive GPCR-mediated inhibition of GABA release occurs by Ca2+-dependent and -independent mechanisms at a hypothalamic synapse.
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DOI：
10.1152/jn.00535.2015
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发表时间：
2016-05
影响因子：
2.5
通讯作者：
Reagan L Pennock;S. Hentges
中科院分区：
文献类型：
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作者：
Reagan L Pennock;S. Hentges
虽然 Gαi/o 偶联受体的激活通常会导致显示急性脱敏的突触后反应，但在激动剂暴露期间，许多 Gαi/o 偶联受体引起的递质释放的突触前抑制得以维持。然而，有一个例外，即在小鼠阿黑皮质素原 (POMC) 神经元中记录的 GABAB 受体 (GABABR) 介导的抑制性突触后电流 (IPSC) 抑制在约 25% 的实验中表现出急性脱敏。为了确定差异效应器耦合是否赋予脱敏敏感性，从 POMC 神经元进行电压钳记录，以比较 μ-阿片受体 (MOR) 和 GABABR 抑制递质释放的机制。 MOR 和 GABABR 介导的释放抑制均不依赖于突触前 K(+) 通道的激活。两种受体在没有外部 Ca(2+) 存在或存在离子霉素诱导的 Ca(2+) 流入的情况下都保持抑制释放的能力，表明释放抑制可以通过 Ca(2+) 独立机制发生。用Sr(2+)代替Ca(2+)来破坏直接发生在释放机器上的G蛋白介导的释放抑制并不会改变MOR或GABAB介导的IPSC抑制，这表明诱发释放的减少可以通过抑制Ca(2+)通道而发生。此外，在存在N-或P/Q-型Ca(2+)通道选择性阻断剂的情况下，两种受体均抑制诱发的IPSC。总而言之，结果表明 MOR 和 GABABR 可以通过抑制钙内流和对释放机制的直接作用来抑制递质释放。此外，由于脱敏和非脱敏突触前受体的偶联相似，差异效应器偶联不太可能导致释放抑制的差异脱敏。
Whereas the activation of Gαi/o-coupled receptors commonly results in postsynaptic responses that show acute desensitization, the presynaptic inhibition of transmitter release caused by many Gαi/o-coupled receptors is maintained during agonist exposure. However, an exception has been noted where GABAB receptor (GABABR)-mediated inhibition of inhibitory postsynaptic currents (IPSCs) recorded in mouse proopiomelanocortin (POMC) neurons exhibit acute desensitization in ∼25% of experiments. To determine whether differential effector coupling confers sensitivity to desensitization, voltage-clamp recordings were made from POMC neurons to compare the mechanism by which μ-opioid receptors (MORs) and GABABRs inhibit transmitter release. Neither MOR- nor GABABR-mediated inhibition of release relied on the activation of presynaptic K(+) channels. Both receptors maintained the ability to inhibit release in the absence of external Ca(2+) or in the presence of ionomycin-induced Ca(2+) influx, indicating that inhibition of release can occur through a Ca(2+)-independent mechanism. Replacing Ca(2+) with Sr(2+) to disrupt G-protein-mediated inhibition of release occurring directly at the release machinery did not alter MOR- or GABAB -mediated inhibition of IPSCs, suggesting that reductions in evoked release can occur through the inhibition of Ca(2+) channels. Additionally, both receptors inhibited evoked IPSCs in the presence of selective blockers of N- or P/Q-type Ca(2+) channels. Altogether, the results show that MORs and GABABRs can inhibit transmitter release through the inhibition of calcium influx and by direct actions at the release machinery. Furthermore, since both the desensitizing and nondesensitizing presynaptic receptors are similarly coupled, differential effector coupling is unlikely responsible for differential desensitization of the inhibition of release.