Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Japan.
J Neurosci. 2010 Feb 24;30(8):3146-55. doi: 10.1523/JNEUROSCI.4140-09.2010.
Fatty acid binding proteins (FABPs) are essential for energy production and long-chain polyunsaturated fatty acid-related signaling in the brain and other tissues. Of various FABPs, heart-type fatty acid binding protein (H-FABP, FABP3) is highly expressed in neurons of mature brain and plays a role in arachidonic acid incorporation into brain and heart cells. However, the precise function of H-FABP in brain remains unclear. We previously demonstrated that H-FABP is associated with the dopamine D(2) receptor long isoform (D2LR) in vitro. Here, we confirm that H-FABP binds to dopamine D(2) receptor (D2R) in brain extracts and colocalizes immunohistochemically with D2R in the dorsal striatum. We show that H-FABP is highly expressed in acetylcholinergic interneurons and terminals of glutamatergic neurons in the dorsal striatum of mouse brain but absent in dopamine neuron terminals and spines in the same region. H-FABP knock-out (KO) mice showed lower responsiveness to methamphetamine-induced sensitization and enhanced haloperidol-induced catalepsy compared with wild-type mice, indicative of D2R dysfunction. Consistent with the latter, aberrant increased acetylcholine (ACh) release and depolarization-induced glutamate (Glu) release were observed in the dorsal striatum of H-FABP KO mice. Furthermore, phosphorylation of CaMKII (Ca(2+)/calmodulin-dependent protein kinase II) and ERK (extracellular signal-regulated kinase) was significantly increased in the dorsal striatum. We confirmed elevated ERK phosphorylation following quinpirole-mediated D2R stimulation in H-FABP-overexpressing SHSY-5Y human neuroblastoma cells. Together, H-FABP is highly expressed in ACh interneurons and glutamatergic terminals, thereby regulating dopamine D2R function in the striatum.
脂肪酸结合蛋白（FABP）对于大脑和其他组织中的能量产生和长链多不饱和脂肪酸相关信号转导至关重要。在各种 FABP 中，心脏型脂肪酸结合蛋白（H-FABP，FABP3）在成熟大脑的神经元中高度表达，并在花生四烯酸掺入脑细胞和心脏细胞中发挥作用。然而，H-FABP 在大脑中的精确功能仍不清楚。我们之前证明 H-FABP 在体外与多巴胺 D2 受体长亚型（D2LR）相关。在这里，我们证实 H-FABP 与脑提取物中的多巴胺 D2 受体（D2R）结合，并在背侧纹状体中与 D2R 免疫组织化学共定位。我们表明，H-FABP 在小鼠大脑背侧纹状体中的乙酰胆碱能中间神经元和谷氨酸能神经元的末梢中高度表达，但在同一区域中的多巴胺神经元末梢和刺突中不存在。与野生型小鼠相比，H-FABP 敲除（KO）小鼠对甲基苯丙胺诱导的敏化反应的反应性较低，并且对氟哌啶醇诱导的僵住作用增强，表明 D2R 功能障碍。与后者一致，在 H-FABP KO 小鼠的背侧纹状体中观察到异常增加的乙酰胆碱（ACh）释放和去极化诱导的谷氨酸（Glu）释放。此外，背侧纹状体中的 CaMKII（Ca2+/钙调蛋白依赖性蛋白激酶 II）和 ERK（细胞外信号调节激酶）磷酸化显著增加。我们在 H-FABP 过表达的 SHSY-5Y 人神经母细胞瘤细胞中证实，在喹吡罗介导的 D2R 刺激后，ERK 磷酸化显著增加。总的来说，H-FABP 在 ACh 中间神经元和谷氨酸能末梢中高度表达，从而调节纹状体中的多巴胺 D2R 功能。
