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G protein-coupled receptor 139 (GPR139), a highly conserved orphan receptor, is predominantly expressed in the habenula of vertebrate species. Habenula is an ancient epithalamic structure, which is critical to comprehending adaptive behaviors in vertebrates. We have previously demonstrated the role of GPR139 agonists in fear-associated decision-making processes in zebrafish. However, how GPR139 signaling in the habenula modulates such adaptive behavioral responses remains unsolved. Fish centrally administered with a synthetic antagonist for human GPR139 (NCRW0005-F05) exhibited significant suppression of odorant cue (alarm substance, AS)-induced fear learning in the conditioned place avoidance paradigm. On the other hand, co-treatment with a GPR139 antagonist and a synthetic agonist for human GPR139 (JNJ-63533054) interrupted the fear conditioning process by significantly reducing locomotion during post-conditioning. Calcium imaging of acute brain slices showed a significant increase in peak amplitude of calcium transients in the habenula upon bath application of either a GPR139 antagonist or agonist. Furthermore, KCl-evoked calcium transients were reduced by the GPR139 antagonist and co-treatment of the GPR139 antagonist–agonist. These results suggest that the GPR139 antagonist did not block the inhibitory action of the GPR139 agonist in the decision-making process during the fear-retrieval phase; however, solitarily, it functions in governing the fear consolidation process via activation of the ventral habenula neurons in zebrafish.

GPR139, a Gq-coupled receptor that is activated by the essential amino acids L-tryptophan and L-phenylalanine, is predominantly expressed in the brain and pituitary. The physiological function of GPR139 remains elusive despite the availability of pharmacological tool agonist compounds and knock-out mice. Whole tissue RNA sequencing data from human, mouse and rat tissues revealed that GPR139 and the dopamine D2 receptor (DRD2) exhibited some similarities in their distribution patterns in the brain and pituitary gland. To determine if there was true co-expression of these two receptors, we applied double in situ hybridization in mouse tissues using the RNAscope® technique. GPR139 and DRD2 mRNA co-expressed in a majority of same cells within part of the dopaminergic mesolimbic pathways (ventral tegmental area and olfactory tubercle), the nigrostriatal pathway (compact part of substantia nigra and caudate putamen), and also the tuberoinfundibular pathway (arcuate hypothalamic nucleus and anterior lobe of pituitary). Both receptors mRNA also co-express in the same cells of the brain regions involved in responses to negative stimulus and stress, such as lateral habenula, lateral septum, interpeduncular nucleus, and medial raphe nuclei. GPR139 mRNA expression was detected in the dentate gyrus and the pyramidal cell layer of the hippocampus as well as the paraventricular hypothalamic nucleus. The functional interaction between GPR139 and DRD2 was studied in vitro using a calcium mobilization assay in cells co-transfected with both receptors from several species (human, rat, and mouse). The dopamine DRD2 agonist did not stimulate calcium response in cells expressing DRD2 alone consistent with the Gi signaling transduction pathway of this receptor. In cells co-transfected with DRD2 and GPR139 the DRD2 agonist was able to stimulate calcium response and its effect was blocked by either a DRD2 or a GPR139 antagonist supporting an in vitro interaction between GPR139 and DRD2. Taken together, these data showed that GPR139 and DRD2 are in position to functionally interact in native tissue.

GPR139, a Gq-coupled receptor that is activated by the essential amino acids L-tryptophan and L-phenylalanine, is predominantly expressed in the brain and pituitary. The physiological function of GPR139 remains elusive despite the availability of pharmacological tool agonist compounds and knock-out mice. Whole tissue RNA sequencing data from human, mouse and rat tissues revealed that GPR139 and the dopamine D2 receptor (DRD2) exhibited some similarities in their distribution patterns in the brain and pituitary gland. To determine if there was true co-expression of these two receptors, we applied double in situ hybridization in mouse tissues using the RNAscope® technique. GPR139 and DRD2 mRNA co-expressed in a majority of same cells within part of the dopaminergic mesolimbic pathways (ventral tegmental area and olfactory tubercle), the nigrostriatal pathway (compact part of substantia nigra and caudate putamen), and also the tuberoinfundibular pathway (arcuate hypothalamic nucleus and anterior lobe of pituitary). Both receptors mRNA also co-express in the same cells of the brain regions involved in responses to negative stimulus and stress, such as lateral habenula, lateral septum, interpeduncular nucleus, and medial raphe nuclei. GPR139 mRNA expression was detected in the dentate gyrus and the pyramidal cell layer of the hippocampus as well as the paraventricular hypothalamic nucleus. The functional interaction between GPR139 and DRD2 was studied in vitro using a calcium mobilization assay in cells co-transfected with both receptors from several species (human, rat, and mouse). The dopamine DRD2 agonist did not stimulate calcium response in cells expressing DRD2 alone consistent with the Gi signaling transduction pathway of this receptor. In cells co-transfected with DRD2 and GPR139 the DRD2 agonist was able to stimulate calcium response and its effect was blocked by either a DRD2 or a GPR139 antagonist supporting an in vitro interaction between GPR139 and DRD2. Taken together, these data showed that GPR139 and DRD2 are in position to functionally interact in native tissue. [ABSTRACT FROM AUTHOR]