Hinkle Patricia M, Pekary A Eugene, Senanayaki Shayani, Sattin Albert
Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Box 711, 601 Elmwood Ave., Rochester, NY 14642, USA.
Brain Res. 2002 May 10;935(1-2):59-64. doi: 10.1016/s0006-8993(02)02454-x.
A large family of TRH-like peptides in the limbic region of rat brain including pGlu-Glu-Pro-NH(2) (EEP), pGlu-Val-Pro-NH(2) (Val(2)-TRH), Leu(2)-TRH, Phe(2)-TRH and Tyr(2)-TRH has recently been discovered. TRH (pGlu-His-Pro-NH(2)) has antidepressant, neuroprotective, analeptic, anticonvulsant, antiamnesic and euphoric properties, and other TRH-like peptides such as EEP exert several of these effects. A new TRH receptor (TRHR2) has been reported which is highly expressed in regions of rat brain that regulate attention and learning, arousal, sleep and processing of sensory information. The TRHR1 predominates in limbic structures involved in regulation of mood and in pituitary. This study examined the possibility that some of the newly discovered TRH-like peptides bind with high affinity to TRHR2, and that this receptor acts as the transducer for some of the CNS effects of this new class of neuropeptides. EEP, Val(2)-TRH and Leu(2)-TRH were analeptics, like TRH, but Phe(2)-TRH and Tyr(2)-TRH were not. The affinity and efficacy of TRH-like peptides for TRHR1 and TRHR2 were measured in HEK293 cells stably expressing these receptors. The IC(50) values of TRH-like peptides for displacement of [3H]TRH from TRHR2 were TRH<<<(Leu(2)-, Phe(2)-TRH)<(Gln(2)-, Ser(2)-TRH)<<(Val(2)-, Tyr(2)-, Arg(2)-, Thr(2)-, and Glu(2)-TRH). The IC(50) for Leu(2)-TRH was about 100 times that for TRH. When tested at the calculated IC(50) values, TRH-like peptides stimulated calcium responses in cells expressing TRHR1 and TRHR2, indicating that the peptides act as weak agonists at both receptors. These results indicate that TRHR1 and TRHR2 do not mediate the behavioral effects of TRH-like peptides.
最近在大鼠脑边缘区域发现了一大类促甲状腺激素释放激素（TRH）样肽，包括焦谷氨酸-谷氨酸-脯氨酸-酰胺（EEP）、焦谷氨酸-缬氨酸-脯氨酸-酰胺（Val(2)-TRH）、亮氨酸-TRH、苯丙氨酸-TRH和酪氨酸-TRH。TRH（焦谷氨酸-组氨酸-脯氨酸-酰胺）具有抗抑郁、神经保护、兴奋、抗惊厥、抗遗忘和欣快特性，其他TRH样肽如EEP也发挥其中一些作用。已报道一种新的TRH受体（TRHR2），其在大鼠脑调节注意力和学习、觉醒、睡眠及感觉信息处理的区域高度表达。TRHR1在参与情绪调节的边缘结构和垂体中占主导。本研究探讨了一些新发现的TRH样肽是否与TRHR2高亲和力结合，以及该受体是否作为这类新神经肽某些中枢神经系统效应的转导器。EEP、Val(2)-TRH和亮氨酸-TRH与TRH一样是兴奋药，但苯丙氨酸-TRH和酪氨酸-TRH不是。在稳定表达这些受体的人胚肾293（HEK293）细胞中测量TRH样肽对TRHR1和TRHR2的亲和力和效能。TRH样肽从TRHR2置换[3H]TRH的半数抑制浓度（IC(50)）值为TRH<<<（亮氨酸-、苯丙氨酸-TRH）<（谷氨酰胺-、丝氨酸-TRH）<<（缬氨酸-、酪氨酸-、精氨酸-、苏氨酸-和谷氨酸-TRH）。亮氨酸-TRH的IC(50)约为TRH的100倍。当以计算出的IC(50)值进行测试时，TRH样肽刺激表达TRHR1和TRHR2的细胞中的钙反应，表明这些肽在两种受体上均作为弱激动剂起作用。这些结果表明TRHR1和TRHR2不介导TRH样肽的行为效应。
