Control of a hippocampal recurrent excitatory circuit by cannabinoid receptor-interacting protein Gap43.
Control of a hippocampal recurrent excitatory circuit by cannabinoid receptor-interacting protein Gap43.
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DOI：
10.1038/s41467-023-38026-2
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发表时间：
2023-04-21
影响因子：
16.6
通讯作者：
Guzman, Manuel
中科院分区：
文献类型：
--
作者：
Maroto, Irene B.;Costas-Insua, Carlos;Berthoux, Coralie;Moreno, Estefania;Ruiz-Calvo, Andrea;Montero-Fernandez, Carlos;Macias-Camero, Andrea;Martin, Ricardo;Garcia-Font, Nuria;Sanchez-Prieto, Jose;Marsicano, Giovanni;Bellocchio, Luigi;Canela, Enric I.;Casado, Vicent;Galve-Roperh, Ismael;Nunez, Angel;Fernandez de Sevilla, David;Rodriguez-Crespo, Ignacio;Castillo, Pablo E.;Guzman, Manuel
1型大麻素受体（CB 1 R）广泛表达于兴奋性和抑制性神经末梢，通过抑制神经递质释放，其激活调节神经回路和大脑功能。虽然CB 1 R与各种细胞内蛋白质的相互作用被认为会改变受体信号传导，但这些蛋白质的身份和作用知之甚少。使用高通量的蛋白质组学分析补充了一系列的体外和体内的方法在小鼠大脑中，我们报告的C-末端，细胞内结构域的CB 1 R与生长相关蛋白43 kDa（GAP 43）的相互作用。CB 1 R-GAP 43的相互作用选择性地发生在苔藓细胞轴突结，其与海马中的齿状颗粒细胞建立兴奋性突触。这种相互作用削弱了CB 1 R介导的苔藓细胞向颗粒细胞传递的抑制，从而抑制了大麻素介导的小鼠抗惊厥活性。因此，GAP 43作为CB 1 R的突触类型特异性调节伙伴，阻碍CB 1 R介导的对海马回路功能的影响。大麻通过CB 1受体影响我们的大脑。在这里，作者确定了一种名为GAP 43的蛋白质，它与CB 1相互作用并阻断其突触功能。这一发现为理解CB 1在大脑中的作用提供了一个概念性的视角。
The type-1 cannabinoid receptor (CB1R) is widely expressed in excitatory and inhibitory nerve terminals, and by suppressing neurotransmitter release, its activation modulates neural circuits and brain function. While the interaction of CB1R with various intracellular proteins is thought to alter receptor signaling, the identity and role of these proteins are poorly understood. Using a high-throughput proteomic analysis complemented with an array of in vitro and in vivo approaches in the mouse brain, we report that the C-terminal, intracellular domain of CB1R interacts specifically with growth-associated protein of 43 kDa (GAP43). The CB1R-GAP43 interaction occurs selectively at mossy cell axon boutons, which establish excitatory synapses with dentate granule cells in the hippocampus. This interaction impairs CB1R-mediated suppression of mossy cell to granule cell transmission, thereby inhibiting cannabinoid-mediated anti-convulsant activity in mice. Thus, GAP43 acts as a synapse type-specific regulatory partner of CB1R that hampers CB1R-mediated effects on hippocampal circuit function. Cannabis impacts our brain by engaging the CB1 receptor. Here, the authors identify a protein called GAP43 that interacts with CB1 and blocks its synaptic functions. This finding provides a conceptual view to understand how CB1 acts in the brain.
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影响因子：
3.1
作者：
Guggenhuber, Stephan;Alpar, Alan;Klugmann, Matthias
通讯作者：
Klugmann, Matthias
影响因子：
5.3
作者：
Domenici, Maria R.;Azad, Shahnaz C.;Rammes, Gerhard
通讯作者：
Rammes, Gerhard
影响因子：
5.3
作者：
Katona, István;Urbán, Gabriella M.;Freund, Tamás F.
通讯作者：
Freund, Tamás F.
DOI：
10.1073/pnas.1400988111
发表时间：
2014-06-03
影响因子：
11.1
作者：
Chiarlone, Anna;Bellocchio, Luigi;Guzman, Manuel
通讯作者：
Guzman, Manuel
DOI：
10.1073/pnas.2017590118
发表时间：
2021-01-26
影响因子：
11.1
作者：
Jensen, Kyle R.;Berthoux, Coralie;Castillo, Pablo E.
通讯作者：
Castillo, Pablo E.