Sanchez William N, Moreno Estefanía, Ciruela-Jardí Marc, Casajuana-Martín Nil, Yauch Anne, Cai Ning-Sheng, Quiroz Cesar, Chang Ya Gin, Casadó Vicent, Pardo Leonardo, Plant Leigh D, Ferré Sergi
Integrative Neurobiology Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
Laboratory of Molecular Neuropharmacology, Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institute of Biomedicine, University of Barcelona, Barcelona, Spain.
Pharmacol Res. 2025 Aug 8;219:107904. doi: 10.1016/j.phrs.2025.107904.
Heteromerization of Gs with Gi protein-coupled receptors has been suggested to be necessary to sustain the canonical Gi-Gs antagonistic interaction at adenylyl cyclase (AC). These heteromers have a tetrameric quaternary structure, composed by two homodimers each one coupled to its corresponding G protein. We describe the heterotetramer formed by the Gi-coupled μ-opioid receptor (MOR) and the Gs-coupled corticotropin releasing factor CRF receptor (CRFR), which also sustains a canonical interaction at AC and reciprocal allosteric interactions between MOR and CRFR ligands. In addition, we found that CRFR can also couple to Gq proteins in the MOR-CRFR heteromer, providing the frame for also canonical Gi-Gq antagonistic interactions that include other effectors, such as phospholipase C and its Ca -dependent signaling, and which control glutamate release in the central amygdala (CeA). The specific pharmacodynamic properties of the MOR-CRFR heteromer, including its sensitivity to S-methadone, as well as its localization in the CeA suggest it might represent a significant pharmacological target for the analgesic, antistressor and antidepressant effects of opioids and the hyperalgesia of opioid withdrawal.
Gs与Gi蛋白偶联受体的异源二聚化被认为是维持腺苷酸环化酶（AC）处典型的Gi - Gs拮抗相互作用所必需的。这些异源二聚体具有四聚体四级结构，由两个同型二聚体组成，每个同型二聚体与其相应的G蛋白偶联。我们描述了由Gi偶联的μ - 阿片受体（MOR）和Gs偶联的促肾上腺皮质激素释放因子CRF受体（CRFR）形成的异源四聚体，它在AC处也维持典型的相互作用以及MOR和CRFR配体之间的相互变构相互作用。此外，我们发现CRFR在MOR - CRFR异源二聚体中也能与Gq蛋白偶联，为包括其他效应器（如磷脂酶C及其钙依赖性信号传导）的典型Gi - Gq拮抗相互作用提供了框架，这些效应器控制着中央杏仁核（CeA）中的谷氨酸释放。MOR - CRFR异源二聚体的特定药效学特性，包括其对S - 美沙酮的敏感性以及其在CeA中的定位，表明它可能是阿片类药物的镇痛、抗应激和抗抑郁作用以及阿片类药物戒断痛觉过敏的重要药理学靶点。
