The histamine H3 receptor modulates dopamine D2 receptor-dependent signaling pathways and mouse behaviors.
The histamine H3 receptor modulates dopamine D2 receptor-dependent signaling pathways and mouse behaviors.
复制标题
DOI：
10.1016/j.jbc.2023.104583
复制
发表时间：
2023-04
影响因子：
4.8
通讯作者：
Pittenger, Christopher
中科院分区：
文献类型：
--
作者：
Xu, Jian;Pittenger, Christopher
组胺H3受体（H3 R）在纹状体的棘状投射神经元（SPNs）中高度富集，在D1受体（D1 R）表达群体和D2受体（D2 R）表达群体中都是如此。H3 R和D1 R之间的交叉作用已在小鼠中在行为水平和生化水平上得到证实。虽然已经描述了H3 R和D2 R共激活后的相互作用行为效应，但这种相互作用的分子机制尚不清楚。在这里，我们表明，选择性激动剂R-（-）-α-甲基组胺二氢溴酸盐激活H3 R减轻D2 R激动剂诱导的运动活动和刻板行为。利用生物化学方法和邻位连接试验，我们证明了小鼠纹状体中存在H3 R-D2 R复合物。此外，我们研究的后果，同时H3 R-D2 R激动的磷酸化水平的几个信号分子，使用免疫组织化学。在D2 R-SPN中，H3 R激动剂处理通过β-arrestin 2依赖性机制调节Akt（丝氨酸/苏氨酸PKB）-糖原合成酶激酶3 β信号转导对D2 R活化的响应，但在D1 R-SPN中不调节。在这些条件下，促分裂原和应激活化蛋白激酶1和rpS 6（核糖体蛋白S6）的磷酸化基本不变。由于Akt-糖原合成酶激酶3 β信号转导与几种神经精神疾病有关，这项工作可能有助于阐明H3 R在调节D2 R功能中的作用，从而更好地理解涉及组胺和多巴胺系统之间相互作用的病理生理学。
The histamine H3 receptor (H3R) is highly enriched in the spiny projection neurons (SPNs) of the striatum, in both the D1 receptor (D1R)–expressing and D2 receptor (D2R)–expressing populations. A crossantagonistic interaction between H3R and D1R has been demonstrated in mice, both at the behavioral level and at the biochemical level. Although interactive behavioral effects have been described upon coactivation of H3R and D2R, the molecular mechanisms underlying this interaction are poorly understood. Here, we show that activation of H3R with the selective agonist R-(−)-α-methylhistamine dihydrobromide mitigates D2R agonist–induced locomotor activity and stereotypic behavior. Using biochemical approaches and the proximity ligation assay, we demonstrated the existence of an H3R–D2R complex in the mouse striatum. In addition, we examined consequences of simultaneous H3R–D2R agonism on the phosphorylation levels of several signaling molecules using immunohistochemistry. H3R agonist treatment modulated Akt (serine/threonine PKB)–glycogen synthase kinase 3 beta signaling in response to D2R activation via a β-arrestin 2–dependent mechanism in D2R-SPNs but not in D1R-SPNs. Phosphorylation of mitogen- and stress-activated protein kinase 1 and rpS6 (ribosomal protein S6) was largely unchanged under these conditions. As Akt–glycogen synthase kinase 3 beta signaling has been implicated in several neuropsychiatric disorders, this work may help clarify the role of H3R in modulating D2R function, leading to a better understanding of pathophysiology involving the interaction between histamine and dopamine systems.
登录
查看更多内容
影响因子：
4.7
作者：
Bolam JP;Ellender TJ
通讯作者：
Ellender TJ
影响因子：
64.8
作者：
Cui, Guohong;Jun, Sang Beom;Jin, Xin;Pham, Michael D.;Vogel, Steven S.;Lovinger, David M.;Costa, Rui M.
通讯作者：
Costa, Rui M.
影响因子：
3.3
作者：
Rapanelli M;Frick L;Jindachomthong K;Xu J;Ohtsu H;Nairn AC;Pittenger C
通讯作者：
Pittenger C
影响因子：
2.5
作者：
Krusong K;Ercan-Sencicek AG;Xu M;Ohtsu H;Anderson GM;State MW;Pittenger C
通讯作者：
Pittenger C
影响因子：
4.8
作者：
CHUANG, TT;LEVINE, H;DEBLASI, A
通讯作者：
DEBLASI, A