The role of the neuropeptide PEN receptor, GPR83, in the reward pathway: Relationship to sex-differences

Fakira, Amanda K.; Peck, Emily G.; Liu, Yutong; Lueptow, Lindsay M.; Trimbake, Nikita A.; Han, Ming–Hu; Calipari, Erin S.; Devi, Lakshmi A.

doi:10.1016/j.neuropharm.2019.107666

Cited by 12 publications

(23 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GPR83 expressed in the central nervous system may play a role in neurological functions, including emotion, learning, reward processing, and metabolism. 17,23 Knockdown of GPR83 in the hypothalamic preoptic area reduces core body temperature and elevates circulating levels of adiponectin. 24 Analysis of GPR83 knockout mice has suggested that the receptor may be involved in stress, reward and learning, 25 and the regulation of systemic energy metabolism.…”

Section: Discussionmentioning

confidence: 99%

A Pilot Screen of a Novel Peptide Hormone Library Identified Candidate GPR83 Ligands

et al. 2020

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

A Pilot Screen of a Novel Peptide Hormone Library Identified Candidate GPR83 Ligands

et al. 2020

View full text Add to dashboard Cite

“…The nucleus accumbens (NAc) is another brain region that contains a high concentration of GPR83 positive cells, and has been strongly implicated in vulnerability and resilience responses to stress (Zhu et al, 2017) as well as anxiety-like behaviors (Xiao et al, 2020). In contrast to the amygdala, we have recently reported that GPR83 is primarily expressed in cholinergic interneurons in the NAc (Fakira et al, 2019). However, a small percentage of neurons were not characterized but recent studies demonstrated that PV + neurons in the striatum indeed express GPR83 (Enterría-Morales et al, 2020).…”

Section: Resultsmentioning

confidence: 99%

“…To date, no small molecule agonists or antagonists for this receptor have been identified, therefore we used a combination of GPR83 global knockout (KO) animals and GPR83 shRNA mediated local knockdown (KD) in the basolateral amygdala (BLA), central nucleus of the amygdala (CeA) and nucleus accumbens (NAc) to study the role of this receptor in anxiety-related behaviors. These brain regions play a role in anxiety, display significant GPR83 expression, and form circuits that encode positive and negative affective valence (Stuber et al, 2011;Tye et al, 2011;Janak and Tye, 2015a;Namburi et al, 2015;Tovote et al, 2015;Beyeler et al, 2016;Lueptow et al, 2018;Fakira et al, 2019). Our initial behavioral studies also included both male and female subjects to determine whether GPR83 plays a differential role in anxiety-related behaviors between the two sexes.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, cells that express GPR83 mRNA also express eGFP. GPR83 knockout (Jackson Labs, Bar Harbor, ME) mice, generated previously (Lu et al, 2007), lack GPR83 protein and mRNA (Gomes et al, 2016;Fakira et al, 2019). Animal protocols were approved by the IACUC at Icahn School of Medicine at Mount Sinai, according to NIH's Guide for the Care and Use of Laboratory Animals.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

PEN receptor GPR83 in anxiety-like behaviors: differential regulation in global vs amygdalar knockdown

Fakira

Lueptow

Trimbake

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Anxiety disorders are prevalent across the United States and result in a large personal and societal burden. Currently, numerous therapeutic and pharmaceutical treatment options exist. However, drugs to classical receptor targets have shown limited efficacy and often come with unpleasant side effects, highlighting the need to identify novel targets involved in the etiology and treatment of anxiety disorders. GPR83, a recently deorphanized receptor activated by the abundant neuropeptide PEN, has also been identified as a glucocorticoid regulated receptor (and named GIR) suggesting that this receptor may be involved in stress-responses that underlie anxiety. Consistent with this, GPR83 null mice have been found to be resistant to stress-induced anxiety. However, studies examining the role of GPR83 within specific brain regions or potential sex differences have been lacking. In this study, we investigate anxiety-related behaviors in male and female mice with global knockout and following local GPR83 knockdown in female mice. We find that a global knockdown of GPR83 has minimal impact on anxiety-like behaviors in female mice and a decrease in anxiety-related behaviors in male mice. In contrast, a local GPR83 knockdown in the basolateral amygdala leads to more anxiety-related behaviors in female mice. Local GPR83 knockdown in the central amygdala or nucleus accumbens showed no significant effect on anxiety-related behaviors. Finally, dexamethasone administration leads to a significant decrease in receptor expression in the amygdala and nucleus accumbens of female mice. Together, our studies uncover a significant, but divergent role for GPR83 in different brain regions in the regulation of anxiety-related behaviors, which is furthermore dependent on sex.

show abstract

“…Thus, it is possible that uterine GPR83 plays a role in pregnancy by regulating ghrelin action as it does in the hypothalamus. More recently, emerging evidence reveals roles for the centrally located GPR83 in regulating dopamine release and morphine reward-learning (24). Thus, GPR83 appears to be a functionally versatile molecule that might have a significant role in regulating pregnancy.…”

mentioning

confidence: 99%

Uterine Gpr83 mRNA is highly expressed during early pregnancy and GPR83 mediates the actions of PEN in endometrial and non-endometrial cells

et al. 2020

View full text Add to dashboard Cite

Objective: To characterize the expression and signaling of uterine GPR83 in vivo in the nonpregnant and pregnant mouse and in vitro in human endometrial and nonendometrial cells. Design: Controlled laboratory study. Setting: Not applicable. Patients: Not applicable. Interventions: None. Main Outcome Measures: Expression of uterine Gpr83 was determined by quantitative polymerase chain reaction throughout the estrous cycle and during early pregnancy in ovarian-stimulated and nonÀovarian-stimulated mice and pregnant and pseudopregnant mice. Expression was also determined in ovariectomized mice after the administration of oil, E2, P4, or E2 þ P4 and in stromal cells following 6 days of in vitro decidualization. GPR83 signaling was studied in human endometrial and embryonic kidney cell lines. Cells were treated by PEN, a GPR83 ligand, and PEN-induced extracellular signal-regulated kinase (ERK) phosphorylation was assayed under conditions that blocked Ga q/11 and/or b-arrestin signaling. Results: Uterine Gpr83 is expressed throughout the estrous cycle and during early pregnancy; expression increases dramatically at the time of uterine receptivity, embryo implantation, and stromal cell decidualization. In the ovariectomized mouse, hormone add-back reveals that Gpr83 expression is highly responsive to the combined treatment of E2 and P4, and studies in the ovarian-stimulated mouse show that expression is also very sensitive to changes in E2 and P4 and is therefore tightly regulated by E2 and P4. At the implantation site, expression is elevated up to D6 of pregnancy and then declines rapidly on D7 and D8, suggesting that if there is any involvement in decidualization, it is likely associated with primary but not secondary stromal cell decidualization. This premise was supported by the observation that stromal cell decidualization in vitro progresses with a decline in Gpr83 expression. In ERa/ PR-expressing endometrial Ishikawa cells, GPR83 mediates PEN signals in a Ga q/11-dependent manner, and studies conducted in HEK 293 cells lacking b-arrestin revealed that GPR83 also signals via a b-arrestinÀdependent manner. When signaling by either one or both pathways is downregulated, cells exhibit a major reduction in responsiveness to PEN treatment, demonstrating that signaling by both pathways is significant. Conclusion: We hypothesize that PEN/GPR83 signaling regulates uterine receptivity, embryo implantation, and primary stromal cell decidualization by coupling to Ga q/11-and b-arrestinÀdependent pathways.

show abstract

The role of the neuropeptide PEN receptor, GPR83, in the reward pathway: Relationship to sex-differences

Cited by 12 publications

References 49 publications

A Pilot Screen of a Novel Peptide Hormone Library Identified Candidate GPR83 Ligands

A Pilot Screen of a Novel Peptide Hormone Library Identified Candidate GPR83 Ligands

PEN receptor GPR83 in anxiety-like behaviors: differential regulation in global vs amygdalar knockdown

Uterine Gpr83 mRNA is highly expressed during early pregnancy and GPR83 mediates the actions of PEN in endometrial and non-endometrial cells

Contact Info

Product

Resources

About