4.5 GPR139
GPR139 is a class A peptide receptor first discovered in 2002 and discretely expressed within the human and rodent brain (Takeda et al., 2002). The highest expression of GPR139 mRNA is observed in the dorsal medial habenula, with lesser expression in the VTA, dorsal striatum, nucleus accumbens, lateral septum, hypothalamus and medial mammillary nucleus (Liu et al., 2015; Matsuo et al., 2005; Susens et al., 2006; Wang et al., 2015). Previous research, using a GPR139 plasmid transfected into CHO-K1 cells, suggested that GPR139 signalling is dependent on a receptor coupling to an inhibitory G-protein and phospholipase C enzyme action, as well as imerization for proper function (Susens et al., 2006). Further, similar to GPR88 signalling, GPR139 interacts with both µ-opioid and dopamine D2 receptors in the brain (Rabiner et al., 2022), also suggesting a role for GPR139 in complex CNS processes. Further research into the interaction between GPR139 and the opioid system found that this receptor activation led to anti-opioid activity in C. elegans . This was conserved in rodents, where deletion of GPR139 in mice potentiated opioid-induced inhibition of neuronal firing (Wang, Lee, Shih, et al., 2019). These data were further corroborated by electrophysiological data from GPR139 KO mice medial habenula neurons, where GPR139 receptor signalling was suggested to prevent µ-opioid receptor-mediated neuronal inhibition via Gq/11 coupling (Stoveken et al., 2020). Further, GPR139 and D2 mRNA are co-expressed in several other brain regions implicated in AUD, including the caudate putamen, lateral septum, lateral habenula, VTA and arcuate nucleus of rats, mice, and humans (Wang, Lee, Kuei, et al., 2019), but their interactions have not been explored in regard to alcohol or substance use in these regions.
GPR139 binding is suggested to not be restricted to one endogenous ligand, and recent research has implicated adrenocorticotropic hormone and melanocyte-stimulating hormone α and β subunits as agonists at this receptor (Nohr et al., 2017). In addition, physiological concentrations of L-tryptophan and L-phenylalanine can activate this receptor (Liu et al., 2015; Shoblock et al., 2019). Nonetheless, GPR139 remains an orphan receptor to date.
Within the medial habenula, GPR139-positive neurons, which also co-express µ-opioid receptor, send indirect downstream projections to the interpeduncular nucleus, where GPR139 receptors are also present (Boulos et al., 2017; Liu et al., 2015). These two brain regions form an important relay centre between limbic systems and midbrain and hindbrain, having roles in addiction, anxiety and emotional processing (Batalla et al., 2017; Bianco & Wilson, 2009; Ehrlich et al., 2018; Fowler & Kenny, 2012). Indeed, signalling between the medial habenula and the interpeduncular nucleus has been associated with alcohol, nicotine, opiate, and stimulant dependence (McLaughlin et al., 2017). Nonetheless, research in alcohol-dependent rats suggested that compulsive-like drinking and decreased withdrawal-induced hyperalgesia was not mediated by the medial habenula-interpeduncular nucleus circuit, but by the activity of GPR139 itself within the medial habenula (Kononoff et al., 2018).
Organic ligands that target GPR139 and present drug-like properties have been developed in recent years. JNJ-63533054 is a small molecule agonist that is orally bioavailable and can cross the blood-brain barrier (Shoblock et al., 2019). A preclinical study reported that JNJ-63533054 reduced escalation of alcohol self-administration in alcohol-dependent male rats, in a dose-dependent manner, when administered systemically (Kononoff et al., 2018). Similarly, Wang et al., (2019) showed that JNJ-63533054 suppressed morphine intake in morphine-dependent mice. These data demonstrate the role of GPR139 in negatively regulating opioid and alcohol intake and highlight the potential of pharmacologically targeting this receptor. Analogous to JNJ-63533054, TAK-041 (also known as NBI-1065846) is a novel potent GPR139 with a favourable pharmacokinetic profile (Reichard et al., 2021). This compound has been reported to increase sociability in mice with social interaction deficits (Reichard et al., 2021) and to increase effort to obtain food in mice that were moderately food deprived (Munster et al., 2022) via GPR139 signalling. Indeed, a potential role for GPR139 in motivational processes has been previously described. Dao and collaborators reported that GPR139 KO mice display profound impairment in gustatory reward acquisition in an operant task that was rescued by TAK-041 delivered orally (Munster et al., 2022). TAK-041 was shown to be safe and well tolerated in healthy volunteers and patients with schizophrenia following Phase I clinical trials (Yin et al., 2022) and has undergone Phase II clinical trials investigating its effects on motivational anhedonia in patients with stable schizophrenia (trial ID NCT03319953) and to determine this ligand effect on amphetamine-induced dopamine release in the brain (ID NCT02959892). Currently, a Phase II trial is assessing the efficacy of TAK-041 in improving symptoms of anhedonia in patients with major depressive disorder, highlighting the pharmacological potential of this molecule.