The oxytocin receptor represents a key hub in the GPCR heteroreceptor network: Potential relevance for brain and behavior
Open accessAbstract
In the last 10 years, it has become increasingly clear that large numbers of axon collaterals extend from the oxytocin (OXT) hypothalamic axons, especially the parvocellular components, to other brain regions. Consequently, the OXT signaling system forms, like other monoamine axons, a rich functional network across several brain regions. In this manuscript, we review the recently indicated higher order G-protein coupled heteroreceptor complexes of the oxytocin receptor (OXTR), and how these, via allosteric receptor-receptor interactions modulate the recognition, signaling, and trafficking of the participating receptor protomers and their potential impact for brain and behavior. The major focus will be on complexes of the OXTR protomer with the dopamine D2 receptor (D2R) protomer and the serotonin 2A (5-HT2AR) and 2C (5-HT2CR) receptor protomers. Specifically, the existence of D2R-OXTR heterocomplexes in the nucleus accumbens and the caudate putamen of rats has led to a postulated function for this heteromer in social behavior. Next, a physical interaction between OXTRs and the growth hormone secretagogue or ghrelin receptor (GHS-R1a) was demonstrated, which consequently was able to attenuate OXTR-mediated Gαq signaling. This highlights the potential of ghrelin-targeted therapies to modulate oxytocinergic signaling with relevance for appetite regulation, anxiety, depression, and schizophrenia. Similarly, evidence for 5-HT2AR-OXTR heteromerization in the pyramidal cell layer of CA2 and CA3 in the dorsal hippocampus and in the nucleus accumbens shell was demonstrated. This complex may offer new strategies for the treatment of both mental disease and social behavior. Finally, the 5-HT2CR-OXTR heterocomplexes were demonstrated in the CA1, CA2, and CA3 regions of the dorsal hippocampus. Future work should be done to investigate the precise functional consequence of region-specific OXTR heteromerization in the brain, as well across the periphery, and whether the integration of neuronal signals in the brain may also involve higher order OXTR-GHS-R1a heteroreceptor complexes including the dopamine (DA), noradrenaline (NA) or serotonin (5-HT) receptor protomers or other types of G-protein coupled receptors (GPCRs).
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Written from the paper’s full text.
TL;DR
This review proposes the oxytocin receptor (OXTR) as a key hub in the GPCR heteroreceptor network, forming higher-order complexes with dopamine D2, ghrelin GHS-R1a, and serotonin 5-HT2A/2C receptors that allosterically modulate signaling. It discusses potential relevance for social behavior, food intake, anxiety, depression, and schizophrenia, while calling for more in vivo validation.
Key findings
- D2R-OXTR heterocomplexes were found in rat nucleus accumbens and caudate putamen; oxytocin at 3 nM increased D2R antagonist maximal binding capacity (Bmax) and increased the affinity of high-affinity D2R agonist binding sites in accumbal membranes, suggesting facilitatory allosteric receptor-receptor interactions relevant to social behavior and anxiety.
- GHS-R1a-OXTR heterocomplex formation attenuated oxytocin-induced calcium mobilization via Gαq signaling, an effect diminished by a GHS-R1a antagonist; this was proposed to involve slower OXTR recycling and/or a switch toward Gαi signaling.
- 5-HT2AR-OXTR heterocomplexes were demonstrated in the pyramidal cell layer of CA2 and CA3 in rat dorsal hippocampus and in nucleus accumbens shell, with attenuation of Gαq-mediated OXTR and 5-HT2AR signaling.
- 5-HT2CR-OXTR heterocomplexes were found in CA1, CA2, and CA3 of dorsal hippocampus, with highest density in CA3; a 5-HT2CR antagonist enhanced oxytocin-induced hypoactivity in mice.
Methods
- Review article; no new primary data are reported. It synthesizes evidence on OXTR heteroreceptor complexes and their allosteric interactions.
- Cited evidence includes in vitro heterologous cell systems (e.g., HEK293 cells), fc-FRET, BRET, in situ proximity ligation assay, immunofluorescence, calcium mobilization and cAMP assays, radioligand binding, and behavioral tests.
- Samples in the reviewed studies include rat nucleus accumbens and caudate putamen, rat dorsal hippocampus, primary hippocampal and hypothalamic cultures from postnatal day 1 Sprague Dawley rats, and mice; the main analysis is narrative synthesis and hypothesis generation.
Limitations
- The paper states that a gap remains in the physiological relevance of many heteroreceptor complexes, with a limited number of in vivo heterodimerization studies compared to identified complexes; future studies should validate complex formation in vivo under healthy and pathophysiological conditions.
- The paper states that future work should investigate the precise functional consequence of region-specific OXTR heteromerization in the brain and periphery, and whether higher-order OXTR-GHS-R1a complexes include dopamine, noradrenaline, or serotonin receptor protomers.
- Evident from the text: many findings rely on in vitro overexpression systems and ex vivo assays, and the proposed trimeric OXTR-D2R-GHS-R1a complexes and hypothalamic GABA circuit for food reward are explicitly hypotheses to be tested in future work.
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Claims the paper makes
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- Interpretationcitation
D2R-OXTR heterocomplexes play a significant role in social behavior.
“Based on the outstanding work of Young and colleagues on the interactions between DA and OXT systems (Young and Wang, 2004) and in line with the results of Romero-Fernandez (Romero-Fernandez et al., 2013), it seems likely that the D2R-OXTR heterocomplexes play a significant role in social behavior.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Young and Wang, 2004
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- cites Romero-Fernandez et al., 2013 source
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- Premisecitation
The OXTR forms heteroreceptor complexes with dopamine D2R, 5-HT2AR, and 5-HT2CR protomers.
“In this review, we will deal with the discovered OXTR heteroreceptor complexes and their function, in which the dopamine D2R protomers (Romero-Fernandez et al., 2013; de la Mora et al., 2016), 5-HT2AR and 5-HT2CR protomers (Chruścicka et al., 2019, 2021; Wallace Fitzsimons et al., 2019) participate”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Oxytocin (3 nM) highly significantly increases the affinity of the high-affinity D2R agonist binding sites in accumbal membranes.
“In 3H-raclopride competition experiments with dopamine (DA), oxytocin (3 nM) highly significantly increased the affinity of the high-affinity D2R agonist binding sites”
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- Premisecitation
Oxytocin increases D2R Gi/o coupling in accumbal membranes.
“It was found that oxytocin increased D2R Gi/o coupling in accumbal membranes, using the GTP gamma S accumulation assay (Romero-Fernandez et al., 2013).”
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- Premisereasoning
The OXT signaling system forms a rich functional network across several brain regions.
“Consequently, the OXT signaling system forms, like other monoamine axons, a rich functional network across several brain regions.”
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- Premisecitation
D2R-OXTR heterocomplexes exist in the nucleus accumbens and the caudate putamen of rats.
“In 2013, evidence was obtained for the existence of D2R-OXTR heterocomplexes in the nucleus accumbens and the caudate putamen (Romero-Fernandez et al., 2013) using in situ proximity ligation assay”
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- Premisecitation
GPCR heteroreceptor complexes (dimers or higher order complexes) via allosteric receptor-receptor interactions modulate the recognition, signaling, and trafficking of the participating receptor protomers.
“An important integrative molecular mechanism in the cellular plasma membrane is represented by GPCR heteroreceptor complexes (dimers or higher order complexes) that via allosteric receptor-receptor interactions modulate the recognition, signaling, and trafficking of the participating receptor protomers with an impact on other participating proteins”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Fuxe et al., 2010a
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- cites Borroto-Escuela et al., 2014 source
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- cites Fuxe and Borroto-Escuela, 2016
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- Premisecitation
Large numbers of axon collaterals extend from the oxytocin (OXT) hypothalamic axons, especially the parvocellular components, to other brain regions.
“In the last 10 years, it has become increasingly clear that large numbers of axon collaterals extend from the oxytocin (OXT) hypothalamic axons, especially the parvocellular components, to other brain regions.”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Oxytocin at 3 nM increases the maximal binding capacity (Bmax) values for the D2R antagonist in accumbal membranes.
“In D2R binding saturation experiments in accumbal membranes using 3H-raclopride (D2R antagonist), oxytocin at 3 nM increased the maximal binding capacity (Bmax) values for the D2R antagonist”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Romero-Fernandez et al., 2013 source
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- Premisecitation
D2R-OXTR heterocomplexes were validated by BRET in HEK293 cells after co-transfection with D2RRluc and OXTRGFP2.
“These results were validated by using the BRET technique in HEK293 cells after co-transfection with D2RRluc and OXTRGFP2 (de la Mora et al., 2016).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites de la Mora et al., 2016 source
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- Premisecitation
Co-expression of the GHS-R1a and the OXTR significantly impairs oxytocin-mediated Gαq signaling.
“Notably, co-expression of the GHS-R1a and the OXTR was shown to significantly impair oxytocin-mediated Gαq signaling (Wallace Fitzsimons et al., 2019).”
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- Premisecitation
Co-location of the GHS-R1a and OXTR protomers was observed in primary hippocampal and hypothalamic cultures of postnatal day 1 Sprague Dawley rats.
“Furthermore, co-location of the two receptor protomers was observed in primary hippocampal and hypothalamic cultures of postnatal day 1 (P1) Sprague Dawley rats.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wallace Fitzsimons et al., 2019 source
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- Premisecitation
GHSR, 5HT2AR and 5HT2CR dimerization with the OXTR results in attenuation of oxytocin-mediated downstream signaling.
“Both, GHSR, 5HT2AR and 5HT2CR dimerization with the OXTR have been shown to result in attenuation of oxytocin-mediated downstream signaling (Figure 2; Chruścicka et al., 2019, 2021; Wallace Fitzsimons et al., 2019; Borroto-Escuela et al., 2021).”
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- cites Chruścicka et al., 2021
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- cites Wallace Fitzsimons et al., 2019 source
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- Premisecitation
In the crystal structure, cholesterol was bound in a pocket produced by transmembrane helices IV and V.
“In the crystal structure, it was possible to observe that the cholesterol was bound in a pocket produced by transmembrane helices IV and V (Waltenspuhl et al., 2020).”
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- Premisecitation
5-HT2CR-OXTR heterocomplexes were demonstrated in the CA1, CA2, and CA3 regions of the dorsal hippocampus.
“Finally, the 5-HT2CR-OXTR heterocomplexes were demonstrated in the CA1, CA2, and CA3 regions of the dorsal hippocampus.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chruścicka et al., 2021
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- Premisecitation
Intravenous OXT administration reduced the circulating levels of ghrelin.
“Interestingly, OXT was previously shown to interact with the orexigenic hormone ghrelin, where intravenous OXT administration reduced the circulating levels of ghrelin (Vila et al., 2009).”
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- Interpretationreasoning
This provides a structural basis for the allosteric modulation produced by cholesterol and Mg2+ in the OXTR.
“This has provided a structural basis for the allosteric modulation produced by cholesterol and Mg2+ in the OXTR”
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The OXTR has a dependence on allosteric modulators like cholesterol and magnesium (Mg2+) for full activation.
“It is of interest that the OXTR has a dependence on allosteric modulators like cholesterol and magnesium (Mg2+) for full activation (Klein et al., 1995a,b; Perez de la Mora et al., 2022).”
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The novel GHS-R1a/OXTR pair was revealed using in vitro approaches and a novel flow cytometry-based fluorescence resonance energy transfer (fc-FRET) technique.
“The novel GHS-R1a/OXTR pair was revealed by the Schellekens group using in vitro approaches and a novel flow cytometry-based fluorescence resonance energy transfer (fc-FRET) technique (Wallace Fitzsimons et al., 2019).”
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- Interpretationcitation
5-HT2AR agonist-induced allosteric inhibition of the OXTR protomer can diminish its increase in social behavior.
“The 5HT2AR agonist-induced allosteric inhibition of the oxytocin receptor protomer can diminish its increase in social behavior (Froemke and Young, 2021).”
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- Premisecitation
In vitro exposure of neurohypophyseal cells to ghrelin resulted in enhanced oxytocin secretion from the cells.
“In contrast, in vitro exposure of neurohypophyseal cells to ghrelin resulted in enhanced oxytocin secretion from the cells (Galfi et al., 2016).”
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- Premisecitation
OXTRs can form functional heteroreceptor complexes with the GHS-R1a.
“In addition, recent evidence from the Schellekens group has shown that the OXTRs can form functional heteroreceptor complexes with the GHS-R1a (Figure 1; Schellekens et al., 2013a,b)”
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- cites Schellekens et al., 2013b
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Wallace Fitzsimons et al. (2019) showed increased trafficking of the OXTR/GHS-R1a pair following co-expression.
“Wallace Fitzsimons et al. (2019) showed increased trafficking of the OXTR/GHS-R1a pair following co-expression (Chruścicka et al., 2018).”
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The anxiolytic effects of quinpirole and oxytocin microinjections into the central amygdala were blocked by co-infusion with the D2R-like antagonist raclopride.
“The anxiolytic effects were blocked by co-infusion with a D2R-like antagonist raclopride in the central amygdala (de la Mora et al., 2016).”
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- Premisecitation
Two conserved residues with negative charges of transmembrane helices I and II of the OXTR were identified.
“In addition, the existence of two conserved residues with negative charges of transmembrane helices I and II of the OXTR were also identified (Waltenspuhl et al., 2020).”
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- Premisecitation
The GHS-R1a also forms heterocomplexes with other GPCRs like dopamine and serotonin receptor subtypes.
“As mentioned above, the GHS-R1a also forms heterocomplexes with other GPCRs like dopamine and serotonin receptor subtypes (Schellekens et al., 2013a, b).”
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- Premisecitation
The reduction of oxytocin-induced calcium mobilization by the GHS-R1a-OXTR heterocomplex was diminished upon administration of a GHS-R1a antagonist.
“This reduction was diminished upon administration of a GHS-R1a antagonist (Wallace Fitzsimons et al., 2019).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wallace Fitzsimons et al., 2019 source
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- Interpretationreasoning
Restoring the faciliatory D2R-OXTR interactions can represent a new type of treatment for excessive anxiety.
“Thus, restoring the faciliatory D2R-OXTR interactions can represent a new type of treatment for excessive anxiety.”
Quote in the paperSubstantial claim - Premisecitation
Formation of the GHS-R1a-OXTR heterocomplex leads to attenuation of oxytocin-induced calcium mobilization mediated via G alpha q signaling.
“Notably, the most significant finding was that the formation of the GHS-R1a-OXTR heterocomplex led to an attenuation of oxytocin-induced calcium mobilization mediated via G alpha q signaling.”
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- Premisecitation
The crystal structure of the human OXTR was established in a complex with the OXTR antagonist retosiban.
“Recently, the crystal structure of the human OXTR was established in a complex with the OXTR antagonist retosiban which is in clinical use for counteraction of labor (Waltenspuhl et al., 2020).”
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The GHS-R1a possesses a high constitutive activity that reaches 50% of its maximal activity.
“Moreover, the GHS-R1a possesses a high constitutive activity that reaches 50% of its maximal activity that can be modulated by dynamic expression and allosteric mechanisms in GPCR-GHS-R1a complexes (Holst et al., 2003; Petersen et al., 2009; Schellekens et al., 2013a,b; Perez de la Mora et al., 2022).”
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Oxytocin administration modulates serotonin (5-HT) synthesis and 5-HT receptor binding potential, resulting in an overall modulation of the serotonergic system.
“Previous data have also demonstrated that oxytocin administration modulates serotonin (5-HT) synthesis and 5-HT receptor binding potential, resulting in an overall modulation of the serotonergic system (Mottolese et al., 2014).”
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- Premisecitation
5-HT2AR-OXTR heteromerization occurs in the pyramidal cell layer of CA2 and CA3 in the dorsal hippocampus and in the nucleus accumbens shell.
“Similarly, evidence for 5-HT2AR-OXTR heteromerization in the pyramidal cell layer of CA2 and CA3 in the dorsal hippocampus and in the nucleus accumbens shell was demonstrated.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chruścicka et al., 2019
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- Premisecitation
5-HT2CR protomer activation allosterically attenuates OXTR G alpha q mediated signaling substantially more strongly than the OXTR agonist allosterically diminishes 5-HT2CR G alpha q signaling.
“The ability of the 5-HT2CR protomer (red) activation to allosterically attenuate the oxytocin receptor protomer G alpha q mediated signaling is substantially stronger (thick arrow) than the ability of the OXTR receptor agonist to allosterically diminish the 5-HT2CR G alpha q signaling (narrow arrow).”
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- Premisecitation
The 5-HT2CR antagonist strongly enhanced the oxytocin receptor agonist-induced reduction of distance traveled and increase in stationary time.
“In line with the biochemical results, the 5-HT2CR antagonist strongly enhanced the oxytocin receptor agonist-induced reduction of distance traveled and increase in stationary time (Chruścicka et al., 2021).”
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- Premisecitation
The 5HT2AR-OXTR heteroreceptor complex was recently discovered.
“The 5HT2AR-OXTR heteroreceptor complex was recently discovered in the laboratory of Dr. Schellekens (Chruścicka et al., 2019).”
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- Premisecitation
Palatable food intake can cause rewards to develop in cortical networks.
“In this way, the palatable food intake can cause rewards to develop in the cortical networks (Schellekens et al., 2013a,b,c; Onaka and Takayanagi, 2019).”
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Co-expression of the 5-HT2CR protomer markedly diminished oxytocin-induced increases in Gαq-mediated calcium mobilization of the OXTR.
“Noteworthy, co-expression of the 5-HT2CR protomer was able to markedly diminish the oxytocin-induced increases in Gαq-mediated calcium mobilization of the OXTR.”
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- Premisecitation
In 2019, GHS-R1a-OXTR heteromerization was found for the first time.
“In 2019 the GHS-R1a-OXTR heteromerization was found for the first time (Wallace Fitzsimons et al., 2019).”
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- Interpretationcitation
The involvement of RTK in the 5-HT and oxytocin receptor-receptor interactions is indicated by evidence that oxytocin can increase the density and length of 5-HT axons during development.
“which indicates the involvement of RTK in the 5-HT and oxytocin receptor-receptor interactions (Eaton et al., 2012).”
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- Interpretationreasoning
The receptor interface mediating the allosteric wave requires an intact 5-HT2CR agonist binding site for the allosteric wave to pass into the OXTR protomer from the 5-HT2CR protomer.
“This suggests that the receptor interface mediating the allosteric wave requires an intact 5-HT2CR agonist binding site for the allosteric wave to pass into the OXTR protomer from the 5-HT2CR protomer.”
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- Premisecitation
There exists a neuronal D2R positive population in the arcuate nucleus of the hypothalamus that can contribute to the ability of cabergoline to inhibit food intake.
“There also exists a neuronal D2R positive population in the arcuate nucleus of the hypothalamus (Romero-Fernandez et al., 2014) that can contribute to the ability of the ergot D2R agonist cabergoline to inhibit food intake (Kern et al., 2015).”
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OXTR-mediated reduction of food intake occurs with termination of the meal.
“The result was an OXTR-mediated reduction of food intake with the termination of the meal.”
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- Premisecitation
A 5-HT2CR antagonist enhanced the hypoactivity induced in mice by oxytocin.
“It was of substantial interest that a 5-HT2CR antagonist enhanced the hypoactivity induced in mice by oxytocin (Figure 2).”
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- Premisecitation
The Schellekens group demonstrated the formation of a 5-HT2CR-OXTR heterocomplex using in vitro heterologous cell expression systems and fc-FRET combined with ex vivo proximity ligation assay.
“The Schellekens group also recently demonstrated the formation of a 5-HT2CR-OXTR heterocomplex, using in vitro heterologous cell expression systems and fc-FRET combined with ex vivo proximity ligation assay (Chruścicka et al., 2021).”
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- Premisecitation
Cellular colocalization of OXTR and 5-HT2AR was found in the plasma membrane and intracellularly, consistent with co-trafficking.
“Next, cellular colocalization of the OXTR and the 5-HT2AR was found not only in the plasma membrane but also intracellularly which is in line with a co-trafficking of both receptors together.”
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- Interpretationcitation
This attenuation is dependent on the specific bidirectional antagonistic receptor-receptor interaction in the complex and not on expression level, fluorescent tags, or gene delivery mode.
“The results indicate that this attenuation is dependent on the specific bidirectional antagonistic receptor-receptor interaction in this complex and not on their expression level, nor on the fluorescent tags or gene delivery mode.”
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- Premisecitation
OXTR and 5-HT2CR have the ability to participate in locomotor activity.
“It was previously demonstrated that OXTR and 5-HT2CR have the ability to participate in locomotor activity (Nebuka et al., 2020).”
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- Premiseown data
A similar but weaker antagonist allosteric event developed when 5-HT activated the 5-HT2CR protomer in the presence of the OXTR protomer forming the heteroreceptor complex.
“A similar but weaker antagonist allosteric event developed when 5-HT activated the 5-HT2CR protomer in the presence of the OXTR protomer forming the heteroreceptor complex (Figure 2).”
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- Premisecitation
None of the receptor antagonists for the two receptor protomers of the 5-HT2AR-OXTR heterocomplex blocked their signaling.
“It should be underlined that none of the receptor antagonists for the two receptor protomers of the 5-HT2AR-OXTR heterocomplex blocked their signaling.”
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- Premisecitation
Functionally, an attenuation of Gαq-mediated OXTR and 5-HT2AR receptor protomer signaling was observed upon formation of the 5-HT2AR-OXTR heteroreceptor complex.
“Functionally, an attenuation of the Gαq-mediated OXTR and 5-HT2AR receptor protomer signaling was observed, upon the formation of this heteroreceptor complex (Chruścicka et al., 2019).”
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- Premisecitation
In the Schellekens lab, the first evidence for a physiological interaction came from fc-FRET-based experiments using HEK293 cells.
“In the Schellekens lab, the first evidence for a physiological interaction came again from fc-FRET-based experiments using HEK293 cells (Chruścicka et al., 2019).”
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- Interpretationcitation
The mechanism is a constitutive allosteric brake on G alpha q signaling in the OXTR protomer made possible through formation of the 5-HT2CR-OXTR heterocomplex.
“The mechanism is the production of a constitutive allosteric brake on the G alpha q signaling in the OXTR protomer made possible through the formation of the 5-HT2CR-OXTR heterocomplex.”
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- Premisecitation
In situ proximity ligation assay demonstrated the relevance of 5-HT2AR-OXTR heterocomplexes in vivo in rodent brains.
“Final evidence was delivered using in situ proximity ligation assay (PLA), which demonstrated the relevance of the 5-HT2AR-OXTR heterocomplexes in vivo in rodent brains.”
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- Premisecitation
Oxytocin can increase the density and length of 5-HT axons during development.
“Evidence suggests that oxytocin can increase the density and length of 5-HT axons during development”
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- Premisecitation
These two neuronal populations project to neurons in the paraventricular hypothalamic nucleus expressing MC4, almost lacking OXTRs.
“These two neuronal populations project to neurons in the paraventricular hypothalamic nucleus expressing melanocortin 4 (MC4), almost lacking the OXTRs (Onaka and Takayanagi, 2019).”
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- Premisecitation
The inhibition on OXTR mediated signaling was restored following pharmacological targeting of the 5-HT2CR using RS102221, a specific 5-HT2CR antagonist.
“Interestingly, the inhibition on OXTR mediated signaling was restored following a pharmacological targeting of the 5-HT2CR using RS102221 a specific 5-HT2CR antagonist.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chruścicka et al., 2021
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- Interpretationreasoning
A constitutive allosteric wave induced by the OXTR, although reduced compared to the wave induced by 5-HT2AR, exists to bring down the 5-HT2CR G alpha q signaling upon activation by 5-HT.
“Thus, also a constitutive allosteric wave-induced by the OXTR, although reduced compared to the wave induced by 5-HT2AR, exists to bring down the 5-HT2CR G alpha q signaling upon activation by 5-HT.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chruścicka et al., 2021
Not checked in the free run.
- Premisecitation
Galanin receptors have been found in the arcuate nucleus of the hypothalamus.
“Furthermore, galanin receptors have been found in the arcuate nucleus of the hypothalamus (Kinney et al., 1998; Leibowitz, 1998)”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Intracerebroventricular injections of galanin-like peptides enhance the release of oxytocin.
“intracerebroventricular injections of galanin-like peptides enhance the release of oxytocin (Onaka et al., 2005).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Onaka et al., 2005 source
Not checked in the free run.
- Premisecitation
Oxytocin receptors are widespread throughout the hypothalamus.
“oxytocin receptors are widespread throughout the hypothalamus (Yoshimura et al., 1993).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Yoshimura et al., 1993 source
Not checked in the free run.
- Premisecitation
Galanin-like peptides can be released by stress from neurons in the arcuate nucleus.
“galanin-like peptides can be released by stress from neurons in the arcuate nucleus”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Onaka et al., 2005 source
Not checked in the free run.
- May combine two claims. 18
- Classified as probably not a substantial claim. 11
May combine two claims.
InterpretationcitationOXTR activation can allosterically inhibit 5-HT2AR protomer signaling and diminish 5-HT2AR signaling with possible antidepressant effects since 5-HT2AR mediates depressive effects.
“The Oxytocin receptor protomer (OXTR) can upon activation allosterically inhibit 5-HT2AR protomer signaling and diminish the 5-HT2AR signaling with possible antidepressant effects since 5-HT2AR mediates depressive effects (Borroto-Escuela et al., 2021; Perez de la Mora et al., 2022).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Borroto-Escuela et al., 2021
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- cites Perez de la Mora et al., 2022
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May combine two claims.
InterpretationreasoningBlockade of 5-HT2CR signaling can enhance oxytocin receptor signaling and produce improvement of social disease.
“Thus, the findings give indications that blockade of 5-HT2CR signaling can enhance oxytocin receptor signaling and produce improvement of social disease.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationThe GHS-R1a can act as a dynamic adapter GPCR to modulate and fine-tune higher order OXTR heteroreceptor complexes across a wide range of functionalities, from social behavior, food intake to mood and reward functions.
“Therefore, It seems possible that the GHS-R1a can act as a dynamic adapter GPCR to modulate and fine-tune higher order OXTR heteroreceptor complexes across a wide range of functionalities, from social behavior, food intake to mood and reward functions (Schellekens et al., 2013b,c).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Schellekens et al., 2013b
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- cites Schellekens et al., 2013c
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May combine two claims.
InterpretationreasoningOXTR crosstalk or dimerization impacts downstream signaling, conferring functional significance in several metabolic and stress-related disorders, including obesity and depression.
“Thus, OXTR crosstalk or dimerization will impact downstream signaling, conferring functional significance in several metabolic and stress-related disorders, including obesity and depression.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningThis raises the possibility of trimeric OXTR-GHS-R1a-D2R heterocomplexes, in addition to heteromeric complexes of GHS-R1a-OXTR, D2R-OXTR, and D2R-GHS-R1a, which may be independent of ghrelin for its signaling.
“This raises the possibility of trimeric OXTR-GHS-R1a-D2R heterocomplexes, in addition to heteromeric complexes of GHS-R1a-OXTR, D2R-OXTR, and D2R-GHS-R1a, which may be independent of ghrelin for its signaling (Figure 1; Holst et al., 2003; Petersen et al., 2009).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Holst et al., 2003
Not checked in the free run.
- cites Petersen et al., 2009
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May combine two claims.
PremisecitationFood intake activates vagal afferents that reach the nucleus tractus solitarius, where A2 noradrenergic neurons project to the hypothalamus, stimulating hypothalamic oxytocin neurons.
“Food intake activates vagal afferents which reach the nucleus tractus solitarius where A2 noradrenergic neurons (Dahlstroem and Fuxe, 1964) project to the hypothalamus, especially those expressing prolactin-releasing peptide (Okuno et al., 2012), where the hypothalamic oxytocin neurons become stimulated (Okuno et al., 2012).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Dahlstroem and Fuxe, 1964
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- cites Okuno et al., 2012 source
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May combine two claims.
InterpretationreasoningThese residues can be a site for Mg2+ via electrostatic interactions, which may allow the development of allosterically enhanced agonist binding.
“These residues can be a site for the Mg2+ via electrostatic interactions, which may allow the development of allosterically enhanced agonist binding.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationClass A and B GPCRs function not only as monomeric entities but can crosstalk with other GPCRs and can form dimers or higher-order oligomers.
“An extensive literature now supports the fact that Class A and B GPCRs function not only as monomeric entities but can crosstalk with other GPCRs and can even form dimers or higher-order oligomers (Terrillon and Bouvier, 2004; Borroto-Escuela et al., 2012, 2014; Schellekens et al., 2013a; Navarro et al., 2018; Milligan et al., 2019; Nemoto et al., 2022).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Terrillon and Bouvier, 2004
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- cites Borroto-Escuela et al., 2012
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- cites Schellekens et al., 2013a
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationUnder special conditions, increased food intake was found.
“Under special conditions, an increased food intake was found (Onaka and Takayanagi, 2019).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Onaka and Takayanagi, 2019
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May combine two claims.
PremisecitationThe fc-FRET signal was not caused by overexpression, random collision, or dimerization of fluorescent proteins.
“It should be noted that the fc-FRET signal was not caused by overexpression, random collision, or dimerization of fluorescent proteins.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chruścicka et al., 2019
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenThe pharmacological relevance of interactions has been studied using downstream analysis, including calcium mobilization assays and cAMP assays.
“The pharmacological relevance of interactions has been equally studied using downstream analysis, including calcium mobilization assays and cAMP assays.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenSingle cell co-expression analysis using mouse and human cortical data from the Allen Brain Atlas has brought some translational validation of potential GPCR co-expression.
“In addition, single cell co-expression analysis using mouse and human cortical data from the Allen Brain Atlas has brought some translational validation of potential GPCR co-expression.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationA specific crosstalk between OXTR and 5-HT2AR exists, and OXTR had already been demonstrated in a D2R-OXTR heterocomplex.
“Therefore, a specific crosstalk between the OXTR and the 5-HT2AR receptors exists and the OXTR had also already been demonstrated in another heterocomplex of D2R-OXTR (Romero-Fernandez et al., 2013; Figures 1, 2).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Romero-Fernandez et al., 2013 source
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PremisecitationUsing proximity ligation assay, 5-HT2CR-OXTR heterocomplexes were present in brain slices in the dorsal hippocampus and the retro-splenial granular and agranular cortex, mainly in the pyramidal cell layer of CA1, CA2, and CA3 with highest density in CA3; PLA signals were also found over some GABA interneurons in oriens and radiatum, especially CA1.
“Using a proximity ligation assay, the 5-HT2CR-OXTR heterocomplexes were clearly present in brain slices in the dorsal hippocampus and the retro-splenial granular and agranular cortex. They were mainly found in the pyramidal cell layer of the CA1, CA2, and CA3 regions with the highest density in the CA3 region.”
- Also stated in: § A novel OXTR-5-HT2CR heterocomplex and its potential function for brain and behavior · plain
“These regions are mainly built up of glutamate neurons. PLA signals were also found over some GABA interneurons mainly scattered in the cell layers of oriens and radiatum, especially of the CA1 region.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chruścicka et al., 2021
Not checked in the free run.
- Also stated in: § A novel OXTR-5-HT2CR heterocomplex and its potential function for brain and behavior · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationComputational approaches for modeling and predicting GPCR dimerization have been provided by the GGIP web server and online resources including the GPCR-HetNet.
“Computational approaches for modeling and predicting GPCR dimerization have been provided by the GGIP web server (Nemoto et al., 2022) and online resources including the GPCR-HetNet (Borroto-Escuela et al., 2014).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Nemoto et al., 2022
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- cites Borroto-Escuela et al., 2014 source
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationFunctional GPCR interactions have revealed physical heteroreceptor complexes with allosteric receptor-receptor interactions between receptor pairs, with each complex resulting in unique alterations to GPCR recognition, signaling, and trafficking.
“Furthermore, functional GPCR interactions have revealed physical heteroreceptor complexes with allosteric receptor-receptor interactions between receptor pairs, with each complex resulting in unique alterations to GPCR recognition, signaling, and trafficking (Fuxe and Borroto-Escuela, 2016, 2018).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Fuxe and Borroto-Escuela, 2016, 2018
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Classified as probably not a substantial claim. May combine two claims.
PremisecitationAgRP/NPY positive neurons in the arcuate nucleus have orexigenic effects and POMC positive arcuate neurons have anorexic effects, playing an important role in food intake.
“primary targets may involve the Agouti-related peptide (AgRP)/neuropeptide Y (NPY) positive neurons in the arcuate nucleus with orexigenic effects and the proopiomelanocortin (POMC) positive arcuate neurons with anorexic effects which play an important role in food intake (Sohn, 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sohn, 2015
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May combine two claims.
PremisecitationIn cells co-expressing the two receptor protomers, basal internalization and trafficking of the OXTR protomer was enhanced, an action diminished by the 5-HT2CR antagonist.
“In line with these results, it was found in cells co-expressing the two receptor protomers that the basal internalization and trafficking of the OXTR protomer was enhanced, an action which was again diminished by the 5-HT2CR antagonist (Chruścicka et al., 2021).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chruścicka et al., 2021
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationGPCR heterocomplexes are increasingly recognized and have important consequences for discovery and development of GPCR-based pharmaceutical targets, as heteromerization is associated with altered GPCR signaling.
“While GPCRs are mainly described as functioning monomers, the formation of GPCR heterocomplexes is increasingly being recognized and has important consequences for the discovery and development of GPCR-based pharmaceutical targets as heteromerization is associated with altered GPCR signaling (Borroto-Escuela et al., 2017, 2018b; Fuxe and Borroto-Escuela, 2018).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Borroto-Escuela et al., 2017, 2018b
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- cites Fuxe and Borroto-Escuela, 2018
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PremisecitationHigh densities of PLA puncta were observed in the pyramidal cell layer of CA2 and CA3 in the rat dorsal hippocampus; substantial densities in the cingulate cortex; and accumulations in the nucleus accumbens shell, indicating the 5-HT2AR-OXTR heterocomplex is found in certain nerve cell populations.
“High densities of PLA puncta were observed in the pyramidal cell layer of CA2 and CA3 in the rat dorsal hippocampus using confocal microscopy.”
- Also stated in: § A novel OXTR-5HT2AR-heterocomplex and its potential function for brain and behavior · plain
“Substantial densities of PLA puncta were also observed in the cingulate cortex around pyramidal nerve cell bodies and along apical dendrites.”
- Also stated in: § A novel OXTR-5HT2AR-heterocomplex and its potential function for brain and behavior · hedged
“In the nucleus accumbens shell also accumulations of PLA puncta with high and low densities were found indicating that the 5-HT2AR-OXTR heterocomplex was found in certain types of nerve cell populations (Chruścicka et al., 2019).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chruścicka et al., 2019
Not checked in the free run.
- Also stated in: § A novel OXTR-5HT2AR-heterocomplex and its potential function for brain and behavior · plain
May combine two claims.
PremisecitationBoth OXTR and 5-HT2CR are expressed in dorsal raphe neurons, with their interactions leading to diminished anxiety.
“In relation to functional relevance, both the OXTR and 5-HT2CR are expressed in dorsal raphe neurons with their interactions leading to diminished anxiety (Yoshida et al., 2009).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Yoshida et al., 2009 source
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PremisecitationBoth 5-HT2AR and OXTR are located in 5-HT neurons, and 5HT2ARs stimulate oxytocin release from paraventricular hypothalamic neurons.
“both GPCRs are located in 5-HT neurons and 5HT2ARs stimulate oxytocin release from the paraventricular hypothalamic neurons (Zhang et al., 2002; Yoshida et al., 2009).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Zhang et al., 2002
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- cites Yoshida et al., 2009 source
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PremisecitationThe 5-HT2CR antagonist used was SB242084, and its specificity was indicated by the observation that this antagonist alone increased locomotor activity.
“The 5-HT2CR antagonist used was SB242084 and the specificity of the effect observed was indicated by the observation that this 5-HT2CR antagonist alone increased locomotor activity (Chruścicka et al., 2021).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chruścicka et al., 2021
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Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningBased on the roles of OXTR and GHS-R1a in the central autonomic and neuroendocrine system, social behavior and food intake, integrative complexes of these receptors can have a special role in the limbic system, the hypothalamus, and the lower brain stem.
“Based on the role of the OXTR and GHS-R1a, especially in the central autonomic and neuroendocrine system, social behavior and food intake, these integrative complexes can have a special role in the limbic system, the hypothalamus, and the lower brain stem.”
Quote in the paperNot a substantial claim- Rests on an assumption: OXTR and GHS-R1a have roles in the central autonomic and neuroendocrine system, social behavior and food intake.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation5-HT and oxytocin interplay in the nucleus accumbens significantly mediates the rewarding aspects of social behavior.
“There are also signs of support for the view that 5-HT and oxytocin interplay in the nucleus accumbens significantly mediate the rewarding aspects of social behavior (Dolen et al., 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Dolen et al., 2013 source
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The paper relies on this without support.
A gap in the physiological relevance of many heteroreceptor complexes remains, with a limited number of in vivo heterodimerization studies published compared to the number of identified heteroreceptor complexes.
“Nevertheless, a gap in the physiological relevance of many heteroreceptor complexes remains, with a limited number of in vivo heterodimerization studies published compared to the number of identified heteroreceptor complexes.”
The paper relies on this without support.
OXTR and GHS-R1a have roles in the central autonomic and neuroendocrine system, social behavior and food intake.
“Based on the role of the OXTR and GHS-R1a, especially in the central autonomic and neuroendocrine system, social behavior and food intake”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
D2R-OXTR heterocomplexes were previously shown to occur in the nucleus accumbens shell and dorsal striatum of the rat in terms of D2R signaling and recognition.
“Previously, heterocomplexes formed by D2R and OXTR protomers were shown to take place in the nucleus accumbens shell and the dorsal striatum of the rat in terms of D2R signaling and recognition (Romero-Fernandez et al., 2013; Borroto-Escuela et al., 2022).”
From Evidence for the existence of facilitatory interactions between the dopamine D2 receptor and the oxytocin receptor in the amygdala of the rat relevance for anxiolytic actions (2023) · cites this paper as Borroto-Escuela et al., 2022
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Proposed extension of the 5-HT2AR complex switches to 5-HT1AR
MinorThe paragraph identifies the novel complex as 5-HT2AR-OXTR, but its proposed higher-order version names 5-HT1AR instead. As written, the proposed complex does not include the serotonin receptor in the complex it is said to extend.
“The 5HT2AR-OXTR heteroreceptor complex was recently discovered in the laboratory of Dr. Schellekens (Chruścicka et al., 2019).”
“It will be interesting to investigate if the GHS-R1a is also a potential heteromeric partner in this novel complex, forming a higher-order GHS-R1a/OXTR/5-HT1AR complex.”
Oxytocin-positive neurons are described as both exclusive to named regions and present in human prefrontal cortex
MinorThe neuroanatomy section says oxytocin-positive nerve cell bodies occur only in the named hypothalamic regions, apart from the bed nucleus of the stria terminalis. The introduction also says oxytocin is expressed in human prefrontal cortical neurons.
“The oxytocin immune-reactive nerve cell bodies only exist in the magnocellular and parvocellular areas of the paraventricular hypothalamic nucleus and in the supraoptic nucleus except for the bed nucleus of the stria terminalis”
“in glutamatergic neurons of the human prefrontal cortex (Zhong et al., 2022).”
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- Authors
- Borroto-Escuela, D. O., Cuesta-Marti, C., Lopez-Salas, A., Chruścicka-Smaga, B., Crespo-Ramírez, M., Tesoro-Cruz, E., Palacios-Lagunas, D. A., Perez de la Mora, M., Schellekens, H., & Fuxe, K.
- Affiliations
- Mexican Social Security Institute (MX)
- Universidad Nacional Autónoma de México (MX)
- University College Cork (IE)
- Corresponding author
- Schellekens, Harriët
- Venue
- Frontiers in Molecular Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2022-12-08
- Volume
- 15
- Pages
- 1055344-1055344
- ISSN
- 1662-5099 (ISSN-L)
- PMC
- PMC9812438
- OpenAlex
- W4313210657
- Cited by
- 38
- References
- 91
- Citations by year
- 2026: 5 · 2025: 15 · 2024: 10 · 2023: 8
- FWCI
- 1.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Molecular Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Lenus, The Irish Health Repository (Dr Steevens Hospital Library) (submittedVersion, cc-by)
- Greater South Information System
- Funders
- Hjärnfonden
- Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México
- Science Foundation Ireland
- Stiftelsen Olle Engkvist Byggmästare
- Karolinska Institutet
- Junta de Andalucàa
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- oxytocin receptor, receptor-receptor interactions, dopamine D2 receptor, 5-HT2A receptor, 5-HT2C receptor, growth hormone secretagogue receptor, GHS-R1a, oxytocin signaling, social behavior, nucleus accumbens, dorsal hippocampus, Gαq signaling, allosteric interactions, brain-behavior relationship
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