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.