Discovery and pharmacological effects of a novel GPR142 antagonist

Murakoshi, Michiko; Kuwabara, Harumi; Nagasaki, Masaru; Xiong, Yu Mei; Reagan, Jeff D.; Maeda, Hiroaki; Nara, Futoshi

doi:10.1080/10799893.2016.1247861

Cited by 13 publications

(9 citation statements)

References 20 publications

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“…However, recent data suggest that serum tryptophan levels are increased in T2DM patients with a higher degree of insulin resistance (Chen et al, 2016), suggesting that inhibition of the receptor could prove beneficial. Furthermore, Gpr142 2/2 mice display reduced levels of sensitivity to a collagen antibody-induced arthritis model of inflammation (Murakoshi et al, 2016). A similar effect was observed with a GPR142 antagonist (CLP-3094) (Murakoshi et al, 2016).…”

Section: J Gpr142mentioning

confidence: 67%

“…Furthermore, Gpr142 2/2 mice display reduced levels of sensitivity to a collagen antibody-induced arthritis model of inflammation (Murakoshi et al, 2016). A similar effect was observed with a GPR142 antagonist (CLP-3094) (Murakoshi et al, 2016). Identification of better tool compounds will enable greater target validation and clarification of the pathophysiological processes controlled by GPR142.…”

Section: J Gpr142mentioning

confidence: 81%

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G Protein–Coupled Receptors Targeting Insulin Resistance, Obesity, and Type 2 Diabetes Mellitus

Riddy¹,

Delerive²,

Summers³

et al. 2017

Pharmacol Rev

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G protein-coupled receptors (GPCRs) continue to be important discovery targets for the treatment of type 2 diabetes mellitus (T2DM). Many GPCRs are directly involved in the development of insulin resistance and -cell dysfunction, and in the etiology of inflammation that can lead to obesity-induced T2DM. This review summarizes the current literature describing a number of well-validated GPCR targets, but also outlines several new and promising targets for drug discovery. We highlight the importance of understanding the role of these receptors in the disease pathology, and their basic pharmacology, which will pave the way to the development of novel pharmacological probes that will enable these targets to fulfill their promise for the treatment of these metabolic disorders.

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Section: J Gpr142mentioning

confidence: 67%

Section: J Gpr142mentioning

confidence: 81%

G Protein–Coupled Receptors Targeting Insulin Resistance, Obesity, and Type 2 Diabetes Mellitus

Riddy¹,

Delerive²,

Summers³

et al. 2017

Pharmacol Rev

View full text Add to dashboard Cite

show abstract

“…200 Cxcr2 knockout mice had attenuated autoantibody-mediated arthritis caused by a function of Cxcr2 neutrophil recruitment, 201 while Gpr142 knockout mice showed reduced arthritis scores and disease incidence in an anti-type II collagen antibody-induced arthritis model alongside decreased inflammatory cytokine production. 202 Mader et al found that while Ccr2 −/− mice had larger and stronger bones than wild-type mice, they reported that Ccr2 loss did not significantly protect against bone loss due to disuse or estrogen loss. 203 Ccr5 deletion was linked to reduced cartilage degeneration postsurgery without significant changes in the degree of synovitis and bone metabolic parameters 204 and promoted osteoclast function in orthodontic tooth movement.…”

Section: Diseases or Dysfunction Caused By Gpcr Mutation Or Deletion mentioning

confidence: 99%

The role of GPCRs in bone diseases and dysfunctions

et al. 2019

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The superfamily of G protein-coupled receptors (GPCRs) contains immense structural and functional diversity and mediates a myriad of biological processes upon activation by various extracellular signals. Critical roles of GPCRs have been established in bone development, remodeling, and disease. Multiple human GPCR mutations impair bone development or metabolism, resulting in osteopathologies. Here we summarize the disease phenotypes and dysfunctions caused by GPCR gene mutations in humans as well as by deletion in animals. To date, 92 receptors (5 glutamate family, 67 rhodopsin family, 5 adhesion, 4 frizzled/taste2 family, 5 secretin family, and 6 other 7TM receptors) have been associated with bone diseases and dysfunctions (36 in humans and 72 in animals). By analyzing data from these 92 GPCRs, we found that mutation or deletion of different individual GPCRs could induce similar bone diseases or dysfunctions, and the same individual GPCR mutation or deletion could induce different bone diseases or dysfunctions in different populations or animal models. Data from human diseases or dysfunctions identified 19 genes whose mutation was associated with human BMD: 9 genes each for human height and osteoporosis; 4 genes each for human osteoarthritis (OA) and fracture risk; and 2 genes each for adolescent idiopathic scoliosis (AIS), periodontitis, osteosarcoma growth, and tooth development. Reports from gene knockout animals found 40 GPCRs whose deficiency reduced bone mass, while deficiency of 22 GPCRs increased bone mass and BMD; deficiency of 8 GPCRs reduced body length, while 5 mice had reduced femur size upon GPCR deletion. Furthermore, deficiency in 6 GPCRs induced osteoporosis; 4 induced osteoarthritis; 3 delayed fracture healing; 3 reduced arthritis severity; and reduced bone strength, increased bone strength, and increased cortical thickness were each observed in 2 GPCR-deficiency models. The ever-expanding number of GPCR mutation-associated diseases warrants accelerated molecular analysis, population studies, and investigation of phenotype correlation with SNPs to elucidate GPCR function in human diseases.

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“…The human receptor orthologs of MIP receptors are GPR139 and GPR142, two orphan GPCRs for which neither the endogenous ligand nor the function has been elucidated. GPR139 is predominantly expressed in specific areas of the human and mouse CNS, including the amygdala and hippocampus, whereas GPR142 displays a more ubiquitous expression both in the CNS and in various peripheral glands and organs [31,58,59]. Interestingly, it has been shown, for example, that avoidance learning in humans correlates with activation of amygdala [31,58,59]…”

Section: Discussionmentioning

confidence: 99%

Myoinhibitory peptide signaling modulates aversive gustatory learning in Caenorhabditis elegans

et al. 2019

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Aversive learning and memories are crucial for animals to avoid previously encountered stressful stimuli and thereby increase their chance of survival. Neuropeptides are essential signaling molecules in the brain and are emerging as important modulators of learned behaviors, but their precise role is not well understood. Here, we show that neuropeptides of the evolutionarily conserved MyoInhibitory Peptide (MIP)-family modify salt chemotaxis behavior in Caenorhabditis elegans according to previous experience. MIP signaling, through activation of the G protein-coupled receptor SPRR-2, is required for short-term gustatory plasticity. In addition, MIP/SPRR-2 neuropeptide-receptor signaling mediates another type of aversive gustatory learning called salt avoidance learning that depends on de novo transcription, translation and the CREB transcription factor, all hallmarks of long-term memory. MIP/SPRR-2 signaling mediates salt avoidance learning in parallel with insulin signaling. These findings lay a foundation to investigate the suggested orphan MIP receptor orthologs in deuterostomians, including human GPR139 and GPR142.

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Discovery and pharmacological effects of a novel GPR142 antagonist

Cited by 13 publications

References 20 publications

G Protein–Coupled Receptors Targeting Insulin Resistance, Obesity, and Type 2 Diabetes Mellitus

G Protein–Coupled Receptors Targeting Insulin Resistance, Obesity, and Type 2 Diabetes Mellitus

The role of GPCRs in bone diseases and dysfunctions

Myoinhibitory peptide signaling modulates aversive gustatory learning in Caenorhabditis elegans

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