Sun Xiaoxuan, Yin Lili, Qiao Zhongjun, Younus Muhammad, Chen Guoqing, Wu Xi, Li Jie, Kang Xinjiang, Xu Huadong, Zhou Li, Li Yinglin, Gao Min, Du Xingyu, Hang Yuqi, Lin Zhaohan, Sun Liyuan, Wang Qinglong, Jiao Ruiying, Wang Lun, Hu Meiqin, Wang Yuan, Huang Rong, Li Yiman, Wu Qihui, Shang Shujiang, Guo Shu, Lei Qian, Shu Haifeng, Zheng Lianghong, Wang Shirong, Zhu Feipeng, Zuo Panli, Liu Bing, Wang Changhe, Zhang Quanfeng, Zhou Zhuan
State Key Laboratory of Membrane Biology, National Biomedical Imaging Center and Institute of Molecular Medicine, College of Future Technology, Peking-Tsinghua Center for Life Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China.
Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, 100191, China.
Adv Sci (Weinh). 2025 Feb;12(7):e2412229. doi: 10.1002/advs.202412229. Epub 2024 Dec 27.
Dopamine (DA) in the striatum is vital for motor and cognitive behaviors. Midbrain dopaminergic neurons generate both tonic and phasic action potential (AP) firing patterns in behavior mice. Besides AP numbers, whether and how different AP firing patterns per se modulate DA release remain largely unknown. Here by using in vivo and ex vivo models, it is shown that the AP frequency per se modulates DA release through the D2 receptor (D2R), which contributes up to 50% of total DA release. D2R has a voltage-sensing site at D131 and can be deactivated in a frequency-dependent manner by membrane depolarization. This voltage-dependent D2R inhibition of DA release is mediated via the facilitation of voltage-gated Ca channels (VGCCs). Collectively, this work establishes a novel mechanism that APs per se modulate DA overflow by disinhibiting the voltage-sensitive autoreceptor D2R and thus the facilitation of VGCCs, providing a pivotal pathway and insight into mammalian DA-dependent functions in vivo.
纹状体中的多巴胺（DA）对运动和认知行为至关重要。中脑多巴胺能神经元在行为小鼠中产生紧张性和相位性动作电位（AP）发放模式。除了AP数量外，不同的AP发放模式本身是否以及如何调节DA释放仍 largely未知。在这里，通过使用体内和体外模型，研究表明AP频率本身通过D2受体（D2R）调节DA释放，D2R对总DA释放的贡献高达50%。D2R在D131处有一个电压感应位点，可通过膜去极化以频率依赖的方式失活。这种电压依赖性的D2R对DA释放的抑制是通过促进电压门控钙通道（VGCCs）介导的。总的来说，这项工作建立了一种新机制，即AP本身通过解除对电压敏感的自身受体D2R的抑制从而促进VGCCs来调节DA溢出，为体内哺乳动物DA依赖性功能提供了关键途径和见解。
