Central-type benzodiazepines and the octadecaneuropeptide modulate the effects of GABA on the release of α-melanocyte-stimulating hormone from frog neurointermediate lobe in vitro
Central-type benzodiazepines and the octadecaneuropeptide modulate the effects of GABA on the release of α-melanocyte-stimulating hormone from frog neurointermediate lobe in vitro
复制标题
中枢型苯二氮卓类药物和十八烷神经肽在体外调节 GABA 对青蛙神经中间叶释放 α-黑素细胞刺激激素的作用
DOI：
10.1016/0306-4522(89)90391-6
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发表时间：
1989
期刊：
影响因子：
3.3
通讯作者：
H. Vaudry
中科院分区：
文献类型：
--
作者：
M. Tonon;S. Adjeroud;M. Lamacz;E. Louiset;J. Danger;L. Desrues;L. Cazin;P. Nicolas;H. Vaudry
使用灌注的青蛙神经中间叶研究了 GABA-苯二氮卓受体复合物在促黑素分泌调节中的作用。 GABAA 激动剂 3-氨基-1 丙磺酸模拟了 GABA 对 α-黑素细胞刺激激素分泌的双相作用：短暂刺激后抑制促黑素激素的分泌。 GABAA 拮抗剂 SR 95531 (10−4M) 抑制 GABA (10−4M) 诱导的 α-黑素细胞刺激激素释放的刺激和抑制。由于巴氯芬 (10−4M) 的抑制作用被 SR 95531 (10−4M) 部分拮抗。似乎 GABA 能控制 α-黑素细胞刺激激素的释放主要是通过激活 GABAA 受体来实现的。 GABA 诱导的 α-黑素细胞刺激激素释放被河豚毒素 (10−5M)、Na 通道阻滞剂或硝苯地平 (10−5M) 抑制。一种电压依赖性 Ca2+ 通道阻滞剂，表明 Na+ 和 Ca2+ 离子参与 GABA 作用的刺激阶段。只有中枢型苯二氮卓结合位点激动剂，例如氯硝西泮 (10−4M)，才能改变 α-黑素细胞刺激激素的释放。事实上，氯硝西泮（10−5 至 10−5M）导致 GABA 诱导的刺激和 α-黑素细胞刺激激素释放的抑制呈剂量依赖性增强。这种增强作用被 GABAA 拮抗剂 SR 95531 (10−4M) 或中枢型苯二氮卓结合位点拮抗剂氟马西尼 (10−4M) 拮抗。而印防己毒素 (10−4M) 仅消除刺激阶段。相比之下，外周型苯二氮卓结合位点激动剂 Ro 5-4864 (10−4M) 无法增强 GABA 对 α-黑素细胞刺激激素分泌的影响。为了研究内源性苯二氮卓结合位点配体在控制 α-黑素细胞刺激激素分泌中的可能参与， 已经开发出十八烷神经肽（一种推定的内源性苯二氮卓结合位点抑制剂）的放射免疫测定法。在神经中间叶提取物中发现了高浓度的十八烷神经肽样物质，表明该肽可能充当 GABA-苯二氮卓受体复合物的调节剂。向灌注的神经中间叶施用合成十八烷神经肽（10−6至10−4M）显着降低了GABA对α-黑素细胞刺激激素释放的影响。此外，氟马西尼 (10−4M) 逆转了十八烷神经肽对 GABA 诱导的 α-黑素细胞刺激激素释放调节的抑制作用。综上所述，这些结果表明，GABA 通过 GABA 受体复合物（包括 GABA 识别位点、Cl 通道和中枢型）作用于青蛙黑素细胞。 苯二氮卓结合位点。苯二氮卓受体的激活有可能调节 GABA 对 α-黑素细胞刺激激素分泌的影响，最终反应取决于所用苯二氮卓受体配体的特性：中枢型苯二氮卓结合位点激动剂会增强对 GABA 的反应，而内源性肽能配体 十八烷神经肽减弱 GABA 的作用。
The involvement of the GABA-benzodiazepine receptor complex in the regulation of melanotropin secretion has been investigated using perfused frog neurointermediate lobes. The GABAAagonist 3-amino-1 propane sulfonic acid mimicked the biphasic effect of GABA on α-melanocyte-stimulating hormone secretion: a brief stimulation followed by an inhibition of melanotropin secretion. The GABAAantagonist SR 95531 (10−4M) inhibited both stimulation and inhibition of α-melanocyte-stimulatmg hormone release induced by GABA (10−4M). Since the inhibitory effect of baclofen (10−4M) was partially antagonized by SR 95531 (10−4M). it appears that the GABAergic control of α-melanocyte-stimulating hormone release is mainly achieved through activation of GABAAreceptors. GABA-induced stimulation of α-melanocyte-stimulating hormone release was inhibited by tetrodotoxin (10−5M), an Na--channel blocker, or nifedipine (10−5M). a voltage-dependent Ca2+-channel blocker, suggesting that Na+and Ca2+ions are involved in the stimulatory phase of GABA action. Only central-type benzodiazepine binding site agonists such as clonazepam (10−4M) modified α-melanocyte-stimulating hormone release. In fact, clonazepam (10−5to 10−5M) led to a dose-dependent potentiation of both GABA-induced stimulation and inhibition of α-melanocyte-stimulating hormone release. This potentiating effect was antagonized by the GABAAantagonist SR 95531 (10−4M) or by the central-type benzodiazepine binding site antagonist flumazenil (10−4M). whereas picrotoxin (10−4M) abolished only the stimulatory phase. In contrast, the peripheral-type benzodiazepine binding site agonist Ro 5-4864 (10−4M) was unable to potentiate the effects of GABA on α-melanocyte-stimulating hormone secretion.To investigate the possible involvement of endogenous benzodiazepine binding site ligands in the control of α-melanocyte-stimulating hormone secretion, a radioimmunoassay for the octadecaneuropeptide, a putative endogenous benzodiazepine binding site inhibitor, has been developed. High concentrations of octadecaneuropeptide-like material were found in neurointermediate lobe extracts, suggesting that this peptide may act as a regulator of the GABA-benzodiazepine receptor complex. The administration of synthetic octadecaneuropeptide (10−6to 10−4M) to perifused neurointermediate lobes markedly reduced the effects of GABA on α-melanocyte-stimulatmg hormone release. In addition, flumazenil (10−4M) reversed the inhibitory action of octadecaneuropeptide on GABA-induced modulation of α-melanocyte-stimulating hormone release.Taken together, these results indicate that GABA acts on frog melanotrophs through a GABA receptor complex including a GABAArecognition site, a Cl-channel and a central-type benzodiazepine binding site. Activation of benzodiazepine receptors has the potential to modulate the effects of GABA on α-melanocyte-stimulating hormone secretion, the final response depending on the properties of the benzodiazepine-receptor ligand used: central-type benzodiazepine binding site agonists cause an enhancement of the response to GABA, whereas the endogenous peptidergic ligand octadecaneuropeptide attenuates the action of GABA.