The habenular G-protein-coupled receptor 151 regulates synaptic plasticity and nicotine intake
The habenular G-protein-coupled receptor 151 regulates synaptic plasticity and nicotine intake
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DOI：
10.1073/pnas.1916132117
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发表时间：
2020-03-10
影响因子：
11.1
通讯作者：
Ibanez-Tallon, Ines
中科院分区：
文献类型：
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作者：
Antolin-Fontes, Beatriz;Li, Kun;Ibanez-Tallon, Ines
缰核是上丘脑中一个古老的小脑区，密集表达烟碱乙酰胆碱受体，对尼古丁的摄入和厌恶至关重要。因此，确定操纵缰活动的策略可能会产生治疗尼古丁成瘾的方法。在这里，我们表明，GPR 151，一个孤儿G蛋白偶联受体（GPCR）高度富集在人类和啮齿动物的缰，表达在突触前膜和突触囊泡，并与突触组件控制囊泡释放和离子转运。Gpr 151的缺失抑制了诱发的神经传递，但增强了自发的微型突触电流，消除了尼古丁诱导的短期可塑性。我们发现GPR 151与G-α抑制蛋白G α（o 1）偶联，以降低小鼠和GPR 151表达细胞系中的环磷酸腺苷（cAMP）水平，这些细胞系适合于配体筛选。Gpr 151基因敲除（KO）小鼠表现出对尼古丁的行为反应减弱，并自我给予更大量的药物，通过缰核中Gpr 151的病毒再表达挽救了表型。这些数据确定GPR 151作为控制尼古丁成瘾脆弱性的缰功能的关键调节剂。
The habenula, an ancient small brain area in the epithalamus, densely expresses nicotinic acetylcholine receptors and is critical for nicotine intake and aversion. As such, identification of strategies to manipulate habenular activity may yield approaches to treat nicotine addiction. Here we show that GPR151, an orphan G-protein-coupled receptor (GPCR) highly enriched in the habenula of humans and rodents, is expressed at presynaptic membranes and synaptic vesicles and associates with synaptic components controlling vesicle release and ion transport. Deletion of Gpr151 inhibits evoked neurotransmission but enhances spontaneous miniature synaptic currents and eliminates short-term plasticity induced by nicotine. We find that GPR151 couples to the G-alpha inhibitory protein G alpha(o1) to reduce cyclic adenosine monophosphate (cAMP) levels in mice and in GPR151-expressing cell lines that are amenable to ligand screens. Gpr151- knockout (KO) mice show diminished behavioral responses to nicotine and self-administer greater quantities of the drug, phenotypes rescued by viral reexpression of Gpr151 in the habenula. These data identify GPR151 as a critical modulator of habenular function that controls nicotine addiction vulnerability.