Orphan Gpr182 suppresses ERK-mediated intestinal proliferation during regeneration and adenoma formation

Kechele, Daniel O.; Blue, R. Eric; Zwarycz, Bailey; Espenschied, Scott T.; Mah, Amanda T.; Siegel, Marni B.; Perou, Charles M.; Ding, Shengli; Magness, Scott T.; Lund, P. Kay; Caron, Kathleen M.

doi:10.1172/jci87588

Cited by 17 publications

(25 citation statements)

References 65 publications

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“…In addition, CXCL12 promoted intestinal epithelial recovery from radiation stress ( 44 ). In the absence of GPR182, these effects are expected to be enhanced as described by Kechele et al ( 11 ).…”

Section: Discussionmentioning

confidence: 84%

“…More-detailed analyses in developing zebrafish and in mice revealed that Gpr182 is preferentially expressed in the vascular endothelium ( 9 , 10 ). Widespread expression in endothelial cells of adult mice was shown using a mouse line expressing β-galactosidase under the control of the Gpr182-promoter ( 11 ), and expression of GPR182 in sinusoidal endothelial cells was reported based on immunohistochemical analysis ( 12 ). Whereas the role of GPR182 in endothelial cells is unknown, GPR182 expression was also reported in intestinal stem cells, where the receptor was shown to negatively regulate proliferation during regeneration and adenoma formation ( 11 ).…”

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confidence: 99%

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GPR182 is an endothelium-specific atypical chemokine receptor that maintains hematopoietic stem cell homeostasis

Mercier

Bonnavion

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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G protein–coupled receptor 182 (GPR182) has been shown to be expressed in endothelial cells; however, its ligand and physiological role has remained elusive. We found GPR182 to be expressed in microvascular and lymphatic endothelial cells of most organs and to bind with nanomolar affinity the chemokines CXCL10, CXCL12, and CXCL13. In contrast to conventional chemokine receptors, binding of chemokines to GPR182 did not induce typical downstream signaling processes, including Gq- and Gi-mediated signaling or β-arrestin recruitment. GPR182 showed relatively high constitutive activity in regard to β-arrestin recruitment and rapidly internalized in a ligand-independent manner. In constitutive GPR182-deficient mice, as well as after induced endothelium-specific loss of GPR182, we found significant increases in the plasma levels of CXCL10, CXCL12, and CXCL13. Global and induced endothelium-specific GPR182-deficient mice showed a significant decrease in hematopoietic stem cells in the bone marrow as well as increased colony-forming units of hematopoietic progenitors in the blood and the spleen. Our data show that GPR182 is a new atypical chemokine receptor for CXCL10, CXCL12, and CXCL13, which is involved in the regulation of hematopoietic stem cell homeostasis.

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Section: Discussionmentioning

confidence: 84%

mentioning

confidence: 99%

GPR182 is an endothelium-specific atypical chemokine receptor that maintains hematopoietic stem cell homeostasis

Mercier

Bonnavion

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…Gene-transcription studies suggest that this receptor may also signal through several canonical G protein pathways [ 34 ], but specific G protein coupling has not been reported. Given the demonstrated importance of GPR182 for cellular proliferation and hematopoiesis [ 35 , 36 ], our results suggest that further studies of GPR182 signaling mechanisms are warranted.…”

Section: Discussionmentioning

confidence: 99%

Constitutive G protein coupling profiles of understudied orphan GPCRs

Jang

Inoue

et al. 2021

PLoS ONE

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A large number of GPCRs are potentially valuable drug targets but remain understudied. Many of these lack well-validated activating ligands and are considered “orphan” receptors, and G protein coupling profiles have not been defined for many orphan GPCRs. Here we asked if constitutive receptor activity can be used to determine G protein coupling profiles of orphan GPCRs. We monitored nucleotide-sensitive interactions between 48 understudied orphan GPCRs and five G proteins (240 combinations) using bioluminescence resonance energy transfer (BRET). No receptor ligands were used, but GDP was used as a common G protein ligand to disrupt receptor-G protein complexes. Constitutive BRET between the same receptors and β-arrestins was also measured. We found sufficient GDP-sensitive BRET to generate G protein coupling profiles for 22 of the 48 receptors we studied. Altogether we identified 48 coupled receptor-G protein pairs, many of which have not been described previously. We conclude that receptor-G protein complexes that form spontaneously in the absence of guanine nucleotides can be used to profile G protein coupling of constitutively-active GPCRs. This approach may prove useful for studying G protein coupling of other GPCRs for which activating ligands are not available.

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“…These transgenic animals were selected for their global and constitutive expression of a green fluorescent protein tag on the intestinal epithelial stem cell marker Lgr5 (Barker et al 2007). A power analysis (G*Power 3.1.9.2) based on previously published and our preliminary data investigating mRNA expression differences between IESCs and other crypt cells show that to achieve a power = 0.8 and a type I error of 0.05, an n = 3 mice per group are needed (Mustata et al 2011;Akcora et al 2013;Tsai et al 2014;Kechele et al 2017;Zhou et al 2018). Animals were single housed in shoebox cages and maintained with ad libitum access to tap water and laboratory chow (Teklad 22/5, Envigo, Madison, WI) on a 12:12 light:dark cycle (lights on 0700) in a climate-controlled room (temperature = 21 AE 2°C and humidity = 50 AE 10%).…”

Section: Animalsmentioning

confidence: 99%

Evidence for a direct effect of the autonomic nervous system on intestinal epithelial stem cell proliferation

2018

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The sympathetic (SNS) and parasympathetic (PNS) branches of the autonomic nervous system have been implicated in the modulation of the renewal of many tissues, including the intestinal epithelium. However, it is not known whether these mechanisms are direct, requiring an interaction between autonomic neurotransmitters and receptors on proliferating epithelial cells. To evaluate the existence of a molecular framework for a direct effect of the SNS or PNS on intestinal epithelial renewal, we measured gene expression for the main autonomic neurotransmitter receptors in this tissue. We separately evaluated intestinal epithelial regions comprised of the stem, progenitor, and mature cells, which allowed us to investigate the distinct contributions of each cell population to this proposed autonomic effect. Notably, we found that the stem cells expressed the receptors for the SNS‐associated alpha2A adrenoreceptor and the PNS‐associated muscarinic acetylcholine receptors (M1 and M3). In a separate experiment, we found that the application of norepinephrine or acetylcholine decreases the expression of cyclin D1, a gene necessary for cell cycle progression, in intestinal epithelial organoids compared with controls (P < 0.05). Together, these results provide evidence of a direct mechanism for the autonomic nervous system influence on intestinal epithelial stem cell proliferation.

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Orphan Gpr182 suppresses ERK-mediated intestinal proliferation during regeneration and adenoma formation

Cited by 17 publications

References 65 publications

GPR182 is an endothelium-specific atypical chemokine receptor that maintains hematopoietic stem cell homeostasis

GPR182 is an endothelium-specific atypical chemokine receptor that maintains hematopoietic stem cell homeostasis

Constitutive G protein coupling profiles of understudied orphan GPCRs

Evidence for a direct effect of the autonomic nervous system on intestinal epithelial stem cell proliferation

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