Endolysosomal TPCs regulate social behavior by controlling oxytocin secretion.
Endolysosomal TPCs regulate social behavior by controlling oxytocin secretion.
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DOI：
10.1073/pnas.2213682120
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发表时间：
2023-02-14
影响因子：
11.1
通讯作者：
Cancela, Jose-Manuel
中科院分区：
文献类型：
--
作者：
Martucci, Lora L.;Launay, Jean-Marie;Kawakami, Natsuko;Sicard, Cecile;Desvignes, Nathalie;Dakouane-Giudicelli, Mbarka;Spix, Barbara;Tetu, Maude;Gilmaire, Franck -Olivier;Paulcan, Sloane;Callebert, Jacques;Vaillend, Cyrille;Bracher, Franz;Grimm, Christian;Fossier, Philippe;de la Porte, Sabine;Sakamoto, Hirotaka;Morris, John;Galione, Antony;Granon, Sylvie;Cancela, Jose-Manuel
催产素囊泡从神经垂体释放到血液中以调节生殖生理，从下丘脑释放到血液中以控制社会行为。在这些生理过程中分泌的催产素囊泡的数量被引发大大增强，其机制还不清楚。在这里，我们发现，内溶酶体双孔通道（TPC）是一个不可分割的组成部分的启动过程，使在TPC的情况下，血浆催产素水平和下丘脑释放下降到非常低的水平。TPC缺失也导致社会缺陷，并表明TPC功能障碍可能有助于社会行为障碍。最后，由于激素替代疗法在很大程度上是无效的，药理TPC驱动的Ca 2+释放可能提供一个有前途的策略，促进催产素信号在社会障碍。催产素（OT）是哺乳动物社会行为的重要调节因子，储存于下丘脑神经元的大致密囊泡（LDCV）中。它响应于活性依赖性Ca 2+内流而释放，但也依赖于从细胞内储存的Ca 2+释放，这引发LDCV进行胞吐作用。尽管其重要性，其分泌的Ca 2+依赖性机制的关键方面仍有待确定。在这里，我们表明，溶酶体周围的树突状LDCV，和内溶酶体双孔通道（TPC）的直接激活提供了关键的Ca 2+信号，以总理OT释放增加可释放的LDCV池，而不直接刺激胞吐。我们观察到TPC基因敲除小鼠血浆OT水平显著降低，下丘脑OT分泌受损，表明神经肽囊泡启动活性依赖性释放的重要性。此外，我们发现，1型代谢型谷氨酸受体的激活维持体树突OT释放招募TPC。引发效应可以通过直接应用烟酸腺嘌呤二核苷酸磷酸（调节TPC的内源性信使）或选择性TPC 2激动剂TPC 2-A1-N来模拟，或通过拮抗剂Ned-19来阻断。缺乏TPC的小鼠表现出受损的母性和社会行为，这是恢复直接OT管理。这项研究证明了溶酶体和TPC在控制神经肽分泌和调节社会行为中的意想不到的作用。
Oxytocin vesicles are released from the neurohypophysis into the bloodstream to regulate reproductive physiology and from the hypothalamus to control social behavior. The number of oxytocin vesicles exocytosed during these physiological processes are greatly potentiated by priming whose mechanism is not well understood. Here we find that endolysosomal two-pore channels (TPCs) are an integral component of the priming process so that in the absence of TPCs, plasma oxytocin levels and hypothalamic release fall to very low levels. TPC deletion also leads to social defects and suggests that TPC dysfunction might contribute to social behavioral disorders. Finally, since hormone replacement therapies are largely ineffective, pharmacological TPC-driven Ca2+ release may provide a promising strategy for boosting oxytocin signaling in social disorders. Oxytocin (OT) is a prominent regulator of many aspects of mammalian social behavior and stored in large dense-cored vesicles (LDCVs) in hypothalamic neurons. It is released in response to activity-dependent Ca2+ influx, but is also dependent on Ca2+ release from intracellular stores, which primes LDCVs for exocytosis. Despite its importance, critical aspects of the Ca2+-dependent mechanisms of its secretion remain to be identified. Here we show that lysosomes surround dendritic LDCVs, and that the direct activation of endolysosomal two-pore channels (TPCs) provides the critical Ca2+ signals to prime OT release by increasing the releasable LDCV pool without directly stimulating exocytosis. We observed a dramatic reduction in plasma OT levels in TPC knockout mice, and impaired secretion of OT from the hypothalamus demonstrating the importance of priming of neuropeptide vesicles for activity-dependent release. Furthermore, we show that activation of type 1 metabotropic glutamate receptors sustains somatodendritic OT release by recruiting TPCs. The priming effect could be mimicked by a direct application of nicotinic acid adenine dinucleotide phosphate, the endogenous messenger regulating TPCs, or a selective TPC2 agonist, TPC2-A1-N, or blocked by the antagonist Ned-19. Mice lacking TPCs exhibit impaired maternal and social behavior, which is restored by direct OT administration. This study demonstrates an unexpected role for lysosomes and TPCs in controlling neuropeptide secretion, and in regulating social behavior.
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影响因子：
64.8
作者：
Carcea I;Caraballo NL;Marlin BJ;Ooyama R;Riceberg JS;Mendoza Navarro JM;Opendak M;Diaz VE;Schuster L;Alvarado Torres MI;Lethin H;Ramos D;Minder J;Mendoza SL;Bair-Marshall CJ;Samadjopoulos GH;Hidema S;Falkner A;Lin D;Mar A;Wadghiri YZ;Nishimori K;Kikusui T;Mogi K;Sullivan RM;Froemke RC
通讯作者：
Froemke RC
影响因子：
5.3
作者：
Bale, TL;Davis, AM;McCarthy, MM
通讯作者：
McCarthy, MM
影响因子：
2.9
作者：
Chabout J;Cressant A;Hu X;Edeline JM;Granon S
通讯作者：
Granon S
影响因子：
2.9
作者：
ARLETTI, R;BENELLI, A;BERTOLINI, A
通讯作者：
BERTOLINI, A
影响因子：
3.7
作者：
Chabout J;Serreau P;Ey E;Bellier L;Aubin T;Bourgeron T;Granon S
通讯作者：
Granon S