title: Heart-type fatty acid binding protein regulates dopamine D2 receptor function in mouse brain.
abstract: 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.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Japan.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Shioda
authors.forename: Yui
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Bert
authors.initials: B
authors.lastname: Binas
authors.forename: Yuji
authors.initials: Y
authors.lastname: Owada
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
mesh_terms: D000109:Acetylcholine / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001923:Brain Chemistry / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D045744:Cell Line, Tumor; D004298:Dopamine / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007395:Interneurons / Q000166:cytology / Q000378:metabolism; D008024:Ligands; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D017072:Neostriatum / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: C493409:Fabp3 protein, mouse; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins; D008024:Ligands; D017448:Receptors, Dopamine D2; D018698:Glutamic Acid; D008694:Methamphetamine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048049:Extracellular Signal-Regulated MAP Kinases; D006220:Haloperidol; D000109:Acetylcholine; D004298:Dopamine