Departamento de Fisiologia e Biofisica, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270-901, Brazil.
Escola de Artes, Ciencias e Humanidades, Universidade de Sao Paulo, Sao Paulo, SP 03828-000, Brazil.
Endocrinology. 2023 Jun 26;164(8). doi: 10.1210/endocr/bqad102.
The RF-amide peptides comprise a family of neuropeptides that includes the kisspeptin (Kp), the natural ligand of kisspeptin receptor (Kiss1r), and the RFamide-related peptide 3 (RFRP-3) that binds preferentially to the neuropeptide FF receptor 1 (Npffr1). Kp stimulates prolactin (PRL) secretion through the inhibition of tuberoinfundibular dopaminergic (TIDA) neurons. Because Kp also has affinity to Npffr1, we investigated the role of Npffr1 in the control of PRL secretion by Kp and RFRP-3. Intracerebroventricular (ICV) injection of Kp increased PRL and LH secretion in ovariectomized, estradiol-treated rats. The unselective Npffr1 antagonist RF9 prevented these responses, whereas the selective antagonist GJ14 altered PRL but not LH levels. The ICV injection of RFRP-3 in ovariectomized, estradiol-treated rats increased PRL secretion, which was associated with a rise in the dopaminergic activity in the median eminence, but had no effect on LH levels. The RFRP-3-induced increase in PRL secretion was prevented by GJ14. Moreover, the estradiol-induced PRL surge in female rats was blunted by GJ14, along with an amplification of the LH surge. Nevertheless, whole-cell patch clamp recordings showed no effect of RFRP-3 on the electrical activity of TIDA neurons in dopamine transporter-Cre recombinase transgenic female mice. We provide evidence that RFRP-3 binds to Npffr1 to stimulate PRL release, which plays a role in the estradiol-induced PRL surge. This effect of RFRP-3 is apparently not mediated by a reduction in the inhibitory tone of TIDA neurons but possibly involves the activation of a hypothalamic PRL-releasing factor.
RF-amide 肽包括 kisspeptin（Kp）在内的一类神经肽家族，Kp 是 kisspeptin 受体（Kiss1r）的天然配体，而 RFamide 相关肽 3（RFRP-3）则优先与神经肽 FF 受体 1（Npffr1）结合。Kp 通过抑制结节漏斗多巴胺能（TIDA）神经元来刺激催乳素（PRL）的分泌。由于 Kp 也与 Npffr1 具有亲和力，我们研究了 Npffr1 在 Kp 和 RFRP-3 控制 PRL 分泌中的作用。侧脑室（ICV）注射 Kp 可增加去卵巢、雌二醇处理大鼠的 PRL 和 LH 分泌。非选择性 Npffr1 拮抗剂 RF9 阻止了这些反应，而选择性拮抗剂 GJ14 改变了 PRL 但没有改变 LH 水平。在去卵巢、雌二醇处理的大鼠中，ICV 注射 RFRP-3 可增加 PRL 分泌，这与中脑隆起处多巴胺能活性的升高有关，但对 LH 水平没有影响。GJ14 可阻止 RFRP-3 诱导的 PRL 分泌增加。此外，GJ14 可削弱雌二醇诱导的雌性大鼠 PRL 激增，并放大 LH 激增。然而，全细胞膜片钳记录显示，RFRP-3 对多巴胺转运蛋白-Cre 重组体转基因雌性小鼠 TIDA 神经元的电活动没有影响。我们提供的证据表明，RFRP-3 与 Npffr1 结合以刺激 PRL 释放，这在雌二醇诱导的 PRL 激增中起作用。RFRP-3 的这种作用显然不是通过降低 TIDA 神经元的抑制性张力来介导的，而是可能涉及激活下丘脑的 PRL 释放因子。
