Department of Neuroscience, Karolinska Institutet. Retzius väg 8, 17177 Stockholm, Sweden.
Biochem Biophys Res Commun. 2010 Mar 19;393(4):767-72. doi: 10.1016/j.bbrc.2010.02.078. Epub 2010 Feb 18.
Previous biochemical, cardiovascular and behavioral work has given evidence for the existence of antagonistic galanin receptor-5-HT1A receptor interactions in the brain. In this study we investigated the existence of GalR1-5-HT1A receptor heteromers and their functional characteristics. In mammalian cells transfected with GFP2-tagged 5-HT1A receptor and YFP-tagged GalR1 receptor, a proximity-based fluorescence resonance energy transfer technique was used and it has been demonstrated that GalR1-5-HT1A receptors heteromerize. Furthermore, signaling by either the mitogen-activated protein kinase (MAPK) or adenylyl cyclase (AC) pathways by these heteromers indicates a trans-inhibition phenomenon through their interacting interface via allosteric mechanisms that block the development of an excessive activation of G(i/o) and an exaggerated inhibition of AC or stimulation of MAPK activity. The presence of these heteromers in the discrete brain regions is postulated based on the existence of GalR-5-HT1A receptor-receptor interactions previously described in the brain and gives rise to explore possible novel therapeutic strategies for treatment of depression by targeting the GalR1-5-HT1A heteromers.
先前的生化、心血管和行为研究为大脑中存在拮抗甘丙肽受体-5-羟色胺 1A 受体相互作用提供了证据。在这项研究中，我们研究了 GalR1-5-HT1A 受体异源二聚体的存在及其功能特征。在转染 GFP2 标记的 5-HT1A 受体和 YFP 标记的 GalR1 受体的哺乳动物细胞中，使用基于邻近的荧光共振能量转移技术已经证明 GalR1-5-HT1A 受体异源二聚化。此外，这些异源二聚体的丝裂原活化蛋白激酶 (MAPK) 或腺苷酸环化酶 (AC) 信号通路表明通过变构机制通过其相互作用界面发生转抑制现象，该机制阻止了 G(i/o)的过度激活和 AC 的过度抑制或 MAPK 活性的刺激的发展。基于先前在大脑中描述的 GalR-5-HT1A 受体-受体相互作用，这些异源二聚体存在于离散的脑区，并提出了通过针对 GalR1-5-HT1A 异源二聚体来探索治疗抑郁症的可能新的治疗策略。
