GPR160 de-orphanization reveals critical roles in neuropathic pain in rodents

Yosten, Gina L. C.; Harada, Caron M.; Haddock, Christopher J.; Giancotti, Luigino Antonio; Kolar, Grant R.; Patel, Ryan; Guo, Chun; Chen, Zhoumou; Zhang, Jinsong; Doyle, Tim; Dickenson, Anthony H.; Samson, Willis K.; Salvemini, Daniela

doi:10.1172/jci133270

Cited by 70 publications

(84 citation statements)

References 30 publications

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“…When examining Trpv1, Trpa1 and Cartpt together, we observed cells expressing Cartpt alone, Trpv1 alone, and triply labeled cells that also contained the gene encoding the recently de-orphaned G-protein coupled receptor Gpr160 (Figure 6B). Gpr160 was examined because it is enriched in sensory ganglia, where it has been proposed to play a role in neuropathic pain (Yosten et al, 2020). In order to investigate the coincidence of nociceptive genes such as Trpv1 and satiety genes such as Glp1r, these two genes were stained together with the ionotropic serotonin receptors Htr3a and Htr3b.…”

Section: Resultsmentioning

confidence: 99%

Comparative Analysis of Dorsal Root, Nodose and Sympathetic Ganglia for the Development of New Analgesics

et al. 2020

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Interoceptive and exteroceptive signals, and the corresponding coordinated control of internal organs and sensory functions, including pain, are received and orchestrated by multiple neurons within the peripheral, central and autonomic nervous systems. A central aim of the present report is to obtain a molecularly informed basis for analgesic drug development aimed at peripheral rather than central targets. We compare three key peripheral ganglia: nodose, sympathetic (superior cervical), and dorsal root ganglia in the rat, and focus on their molecular composition using next-gen RNA-Seq, as well as their neuroanatomy using immunocytochemistry and in situ hybridization. We obtained quantitative and anatomical assessments of transmitters, receptors, enzymes and signaling pathways mediating ganglion-specific functions. Distinct ganglionic patterns of expression were observed spanning ion channels, neurotransmitters, neuropeptides, G-protein coupled receptors (GPCRs), transporters, and biosynthetic enzymes. The relationship between ganglionic transcript levels and the corresponding protein was examined using immunohistochemistry for select, highly expressed, ganglion-specific genes. Transcriptomic analyses of spinal dorsal horn and intermediolateral cell column (IML), which form the termination of primary afferent neurons and the origin of preganglionic innervation to the SCG, respectively, disclosed pre- and post-ganglionic molecular-level circuits. These multimodal investigations provide insight into autonomic regulation, nodose transcripts related to pain and satiety, and DRG-spinal cord and IML-SCG communication. Multiple neurobiological and pharmacological contexts can be addressed, such as discriminating drug targets and predicting potential side effects, in analgesic drug development efforts directed at the peripheral nervous system.

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Section: Resultsmentioning

confidence: 99%

Comparative Analysis of Dorsal Root, Nodose and Sympathetic Ganglia for the Development of New Analgesics

et al. 2020

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“…Conversely, blocking endogenous CART signaling within the NTS using CART antibody resulted in a dose-dependent increase in food intake compared with saline. Although there is solid evidence concerning the identity of the CART receptor (Yosten et al, 2020), the absence of a viable antagonist necessitates the use of CART antibody. This approach has previously been used to immunoneutralize CART-induced anorexia centrally (Kristensen et al, 1998), and we validated this approach by demonstrating that pre-incubating CART antibody with CART peptide abolished the stimulatory effect of intraNTS CART antibody on food intake.…”

Section: Discussionmentioning

confidence: 99%

Blunted Vagal Cocaine- and Amphetamine-Regulated Transcript Promotes Hyperphagia and Weight Gain

et al. 2020

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“…In addition to the oGPCRs discussed in this review, a few more have been proposed to be activated by endogenous ligands that were previously implicated in anxiety and mood disorders. Among these oGPCRs, GPR160 has recently been suggested as the receptor for cocaine- and amphetamine-regulated transcript peptide (CARTp), a widely distributed ligand in the central nervous system [ 229 ]. At the molecular level, CARTp was previously shown to activate an undefined Gi/o-coupled receptor [ 230 ], while the treatments of cells expressing endogenous GPR160 stimulated ERK phosphorylation, an effect that was attenuated by co-transfection with GPR160-specific siRNA [ 229 ].…”

Section: Discussionmentioning

confidence: 99%

“…Among these oGPCRs, GPR160 has recently been suggested as the receptor for cocaine- and amphetamine-regulated transcript peptide (CARTp), a widely distributed ligand in the central nervous system [ 229 ]. At the molecular level, CARTp was previously shown to activate an undefined Gi/o-coupled receptor [ 230 ], while the treatments of cells expressing endogenous GPR160 stimulated ERK phosphorylation, an effect that was attenuated by co-transfection with GPR160-specific siRNA [ 229 ]. Although the direct role of GPR160 in controlling depressive-like behavior has not been explored, there is evidence pointing at CARTp in the regulation of stress responses and anxiety [ 231 , 232 , 233 , 234 ].…”

Section: Discussionmentioning

confidence: 99%

Orphan G Protein Coupled Receptors in Affective Disorders

Watkins

Orlandi

2020

Genes

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G protein coupled receptors (GPCRs) are the main mediators of signal transduction in the central nervous system. Therefore, it is not surprising that many GPCRs have long been investigated for their role in the development of anxiety and mood disorders, as well as in the mechanism of action of antidepressant therapies. Importantly, the endogenous ligands for a large group of GPCRs have not yet been identified and are therefore known as orphan GPCRs (oGPCRs). Nonetheless, growing evidence from animal studies, together with genome wide association studies (GWAS) and post-mortem transcriptomic analysis in patients, pointed at many oGPCRs as potential pharmacological targets. Among these discoveries, we summarize in this review how emotional behaviors are modulated by the following oGPCRs: ADGRB2 (BAI2), ADGRG1 (GPR56), GPR3, GPR26, GPR37, GPR50, GPR52, GPR61, GPR62, GPR88, GPR135, GPR158, and GPRC5B.

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GPR160 de-orphanization reveals critical roles in neuropathic pain in rodents

Cited by 70 publications

References 30 publications

Comparative Analysis of Dorsal Root, Nodose and Sympathetic Ganglia for the Development of New Analgesics

Comparative Analysis of Dorsal Root, Nodose and Sympathetic Ganglia for the Development of New Analgesics

Blunted Vagal Cocaine- and Amphetamine-Regulated Transcript Promotes Hyperphagia and Weight Gain

Orphan G Protein Coupled Receptors in Affective Disorders

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