Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke/National Institutes of Health, Bethesda, MD 20892.
eNeuro. 2022 Mar 3;9(2). doi: 10.1523/ENEURO.0461-21.2022. Print 2022 Mar-Apr.
Gonadotropin-releasing hormone (GnRH)-secreting neurons control fertility. The release of GnRH peptide regulates the synthesis and release of both luteinizing hormone (LH) and Follicle stimulation hormone (FSH) from the anterior pituitary. While it is known that dopamine regulates GnRH neurons, the specific dopamine receptor subtype(s) involved remain unclear. Previous studies in adult rodents have reported juxtaposition of fibers containing tyrosine hydroxylase (TH), a marker of catecholaminergic cells, onto GnRH neurons and that exogenous dopamine inhibits GnRH neurons postsynaptically through dopamine D1-like and/or D2-like receptors. Our microarray data from GnRH neurons revealed a high level of transcripts [i.e., dopamine D4 receptor (D4R)]. Single-cell RT-PCR and immunocytochemistry confirmed GnRH cells express the transcript and protein, respectively. Calcium imaging identified changes in GnRH neuronal activity during application of subtype-specific dopamine receptor agonists and antagonists when GABAergic and glutamatergic transmission was blocked. Dopamine, dopamine with D1/5R-specific or D2/3R-specific antagonists or D4R-specific agonists decreased the frequency of calcium oscillations. In contrast, D1/5R-specific agonists increased the frequency of calcium oscillations. The D4R-mediated inhibition was dependent on G protein coupling, while the D1/5R-mediated excitation required G protein coupling. Together, these results indicate that D4R plays an important role in the dopaminergic inhibition of GnRH neurons.
促性腺激素释放激素 (GnRH) 神经元控制着生育能力。 GnRH 肽的释放调节黄体生成素 (LH) 和卵泡刺激素 (FSH) 在前垂体中的合成和释放。虽然已知多巴胺调节 GnRH 神经元，但涉及的特定多巴胺受体亚型仍不清楚。以前在成年啮齿动物中的研究报告称，含有酪氨酸羟化酶 (TH) 的纤维与 GnRH 神经元并列，TH 是儿茶酚胺能细胞的标志物，外源性多巴胺通过多巴胺 D1 样和/或 D2 样受体在后突触抑制 GnRH 神经元。我们从 GnRH 神经元获得的微阵列数据显示了高水平的 转录本 [即多巴胺 D4 受体 (D4R)]。单细胞 RT-PCR 和免疫细胞化学分别证实了 GnRH 细胞表达 转录本和蛋白。当 GABA 能和谷氨酸能传递被阻断时，钙成像鉴定出应用特定于亚型的多巴胺受体激动剂和拮抗剂时 GnRH 神经元活性的变化。多巴胺、多巴胺与 D1/5R 特异性或 D2/3R 特异性拮抗剂或 D4R 特异性激动剂降低钙振荡的频率。相比之下，D1/5R 特异性激动剂增加了钙振荡的频率。D4R 介导的抑制依赖于 G 蛋白偶联，而 D1/5R 介导的兴奋需要 G 蛋白偶联。总之，这些结果表明 D4R 在多巴胺对 GnRH 神经元的抑制中起着重要作用。
