Wang Yueyue, Zhang Yalan, Li Wenxue, Salovska Barbora, Zhang Jianan, Li Tongqing, Li Hengyi, Liu Yansheng, Kaczmarek Leonard K, Pusztai Lajos, Klein Daryl E
Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA; Breast Medical Oncology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA.
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
Mol Cell. 2025 Jan 2;85(1):166-176.e5. doi: 10.1016/j.molcel.2024.11.016. Epub 2024 Dec 5.
The rare γ-aminobutyric acid type-A receptor (GABAR) subunit π (GABRP) is highly expressed in certain cancers, where it stimulates growth through extracellular-regulated kinase (ERK) signaling by an uncharacterized pathway. To elucidate GABRP's signaling mechanism, we determined cryoelectron microscopy (cryo-EM) structures of GABRP embedded in native nanodiscs, both in the presence and absence of GABA. Structurally, GABRP homopentamers closely resemble heteropentameric GABAR anion channels, transitioning from a closed "resting" state to an open "active" state upon GABA binding. However, functional assays reveal that GABRP responds more like a type-B metabotropic receptor. At physiological concentrations of GABA, chloride flux is not detected. Rather, GABRP activates a G-protein-coupled pathway leading to ERK signaling. Ionotropic activity is only triggered at supraphysiological GABA concentrations, effectively decoupling it from GABRP's signaling functions. These findings provide a structural and functional blueprint for GABRP, opening new avenues for targeted inhibition of GABA growth signals in GABRP-positive cancers.
罕见的γ-氨基丁酸A型受体（GABAR）亚基π（GABRP）在某些癌症中高度表达，它通过一种未知途径的细胞外调节激酶（ERK）信号传导来刺激生长。为了阐明GABRP的信号传导机制，我们确定了嵌入天然纳米盘的GABRP在存在和不存在GABA情况下的冷冻电子显微镜（cryo-EM）结构。在结构上，GABRP同五聚体与异五聚体GABAR阴离子通道非常相似，在结合GABA后从关闭的“静止”状态转变为开放的“活性”状态。然而，功能分析表明，GABRP的反应更像是B型代谢型受体。在生理浓度的GABA下，未检测到氯离子通量。相反，GABRP激活一条导致ERK信号传导的G蛋白偶联途径。离子通道活性仅在超生理浓度的GABA下触发，从而有效地将其与GABRP的信号功能解耦。这些发现为GABRP提供了结构和功能蓝图，为在GABRP阳性癌症中靶向抑制GABA生长信号开辟了新途径。
