Li Xiaona, Winters Nathan D, Pandey Shubhi, Lankford Colten, Stoveken Hannah M, Smith Emery, Chang Chu-Ting, Zucca Stefano, Scampavia Louis, Spicer Timothy, Martemyanov Kirill A
Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA.
Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA.
Nat Commun. 2025 Jul 23;16(1):6786. doi: 10.1038/s41467-025-62133-x.
The endogenous opioid system provides powerful control over emotions, nociception, and motivation among many other fundamental nervous system functions. Its major components include a panel of opioid peptides that activate four canonical inhibitory opioid receptors. However, its regulatory principles are not fully understood including the existence of additional receptors and other elements. In this study we report the identification of a receptor for the opioid peptide dynorphin. By conducting a screen of a custom library of neuropeptides, we found that orphan receptor GPR139 binds to and is activated by a series of dynorphin peptides. Unlike other opioid receptors, GPR139 couples to Gq/11 and avoids β-arrestin, providing excitatory signaling that homeostatically scales the inhibitory response of neurons to dynorphin. This introduces a non-canonical dynorphin receptor as an essential component of the opioid system.
内源性阿片系统对情绪、痛觉感受和动机以及许多其他基本神经系统功能具有强大的控制作用。其主要组成部分包括一组可激活四种典型抑制性阿片受体的阿片肽。然而，其调节原理尚未完全明确，包括是否存在其他受体和其他元件。在本研究中，我们报告了阿片肽强啡肽受体的鉴定。通过对一个定制的神经肽文库进行筛选，我们发现孤儿受体GPR139可与一系列强啡肽肽结合并被其激活。与其他阿片受体不同，GPR139与Gq/11偶联并避开β-抑制蛋白，提供兴奋性信号，从而稳态调节神经元对强啡肽的抑制反应。这引入了一种非典型的强啡肽受体作为阿片系统的重要组成部分。
