Assessment of a small molecule melanocortin-4 receptor-specific agonist on energy homeostasis

Cepoi, David; Phillips, Teresa A.; Cismowski, Mary J.; Goodfellow, Val S.; Ling, N; Cone, Roger D.; Fan, Wei

doi:10.1016/j.brainres.2003.10.041

Cited by 29 publications

(16 citation statements)

References 25 publications

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“…Interestingly, the amount of peptide versus nonpeptide agonists required to elicit feeding in rodents does not correlate with their in vitro profile with nonpeptides exhibiting decreased potency in vivo (Cepoi et al, 2004). However, further analysis of both in vitro and in vivo data are required before deductions can be drawn.…”

Section: Discussionmentioning

confidence: 99%

Functional Selectivity of Melanocortin 4 Receptor Peptide and Nonpeptide Agonists: Evidence for Ligand-Specific Conformational States

Nickolls¹,

Fleck²,

Hoare³

et al. 2005

J Pharmacol Exp Ther

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Agonists of the melanocortin 4 (MC4) receptor have potential pharmaceutical benefit in the treatment of obesity and sexual dysfunction. In this study, we have compared the ability of a number of peptide and nonpeptide agonists to activate a FLAG-tagged human MC4 (FMC4) receptor, as measured by both cAMP accumulation and calcium mobilization using a fluorometric imaging plate reader (FLIPR). In addition, we have analyzed the ability of these agonists to cause receptor internalization, as measured by fluorescence-activated cell sorting analysis. The endogenous agonist ␣-melanocortin-stimulating hormone (␣-MSH) increased cAMP accumulation, calcium mobilization, and receptor internalization in a dose-dependent manner in human embryonic kidney 293 cells expressing the FMC4 receptor. The activity of the other agonists varied considerably in these assays, and overall, the potency and intrinsic activity of the agonists in the cAMP accumulation assays did not correlate with their potency or intrinsic activity in either the FLIPR or receptor internalization assays. Agonists could be clearly separated into two functional classes based on their structure. Peptide agonists ␤-MSH, des-acetyl-␣-MSH, and [Nle 4 , D-Phe 7 ]-␣-melanocortin-stimulating hormone exhibited 80 to 112% of the maximal ␣-MSH response in cAMP accumulation and 62 to 96% in FLIPR assays and were able to cause 75 to 118% of receptor internalization induced by ␣-MSH. Conversely, although the nonpeptide agonists exhibited 73 to 149% of the ␣-MSH response in the cAMP accumulation assays, they were significantly impaired in the FLIPR (7-40%) and receptor internalization (Ϫ5-38%) assays. These findings demonstrate an important difference in activation and internalization of the MC4 receptor by nonpeptide versus peptide agonists and provides evidence of agonist-specific conformational states.The melanocortin 4 receptor (MC4R) is a member of the seven transmembrane receptor family that initiate signal transduction through activation of heterotrimeric G proteins. There are four additional members of the melanocortin receptor subfamily, distinguishable by their distribution and physiology. Melanocortin receptors are all activated by one or more pro-opiomelanocortin-derived peptides, which include ␣-, ␤-, and ␥-melanocortin-stimulating hormone (MSH). In addition, the melanocortin receptors are regulated by the antagonists/inverse agonists, AGRP and agouti (Lu et al., 1994;Ollmann et al., 1997).The melanocortin receptors all signal through G␣ s , which stimulates the production of cAMP by adenylate cyclase. The MC3 receptor also functions through phospholipase C to increase intracellular calcium (Konda et al., 1994). Likewise, the MC4 receptor mediates an increase in intracellular calcium, but reportedly through a cholera toxin-sensitive pathway rather than phospholipase C (Mountjoy et al., 2001).

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Section: Discussionmentioning

confidence: 99%

Functional Selectivity of Melanocortin 4 Receptor Peptide and Nonpeptide Agonists: Evidence for Ligand-Specific Conformational States

Nickolls¹,

Fleck²,

Hoare³

et al. 2005

J Pharmacol Exp Ther

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“…A cannula with an obturator stylet inside (RWD Life Science Co., LTD) was implanted into the third ventricle of 8-week-old male mice as described (77). After 1 week of recovery, mice received daily intraventricle injection of 1 μg MTII 1 hour before the dark phase.…”

Section: Methodsmentioning

confidence: 99%

Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity

Cui¹,

Ding²,

Shu³

et al. 2016

Journal of Clinical Investigation

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“…Eleven-to twelve-week-old female mice anesthetized by intraperitoneal injection of 0.15 ml of mouse cocktail (ketamine-xylazine-saline, 1:1:8) were ovariectomized and then kept anesthetized with isoflurane during the icv cannulation procedure. The mice were placed into a stereotaxic instrument (Cartesian Instruments, Bend, OR), the cranial surface cleaned, and a cannula placed into the third ventricle as described previously (Cepoi et al, 2004). In brief, a small hole was drilled, and a sterile stainless steel guide cannula (25 gauge, 1.1 cm long, with an obturator stylet placed within) was implanted at midline, 0.825 mm posterior to bregma and 4.8 mm below bregma based on Franklin and Paxinos (1997).…”

Section: -Ht 2c Receptor Signaling In Hypothalamic Pomc Neurons 887mentioning

confidence: 99%

Serotonin 5-Hydroxytryptamine_2CReceptor Signaling in Hypothalamic Proopiomelanocortin Neurons: Role in Energy Homeostasis in Females

et al. 2007

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Hypothalamic proopiomelanocortin (POMC) neurons play a critical role in the regulation of energy balance, and there is a convergence of critical synaptic input including GABA and serotonin on POMC neurons to regulate their output. We found previously that 17␤-estradiol (E 2 ) reduced the potency of the GABA B receptor agonist baclofen to activate G protein-coupled inwardly rectifying potassium (GIRK) channels in hypothalamic POMC neurons through a membrane estrogen receptor (mER) via a G␣ q phospholipase C (PLC)-protein kinase C␦-protein kinase A pathway. We hypothesized that the mER and neurotransmitter receptor signaling pathways converge to control energy homeostasis. Because 5-HT 2C receptors mediate many of the effects of serotonin in POMC neurons, we elucidated the common signaling pathways of E 2 and 5-HT in guinea pigs using single-cell reverse transcription-polymerase chain reaction (RT-PCR), real time RT-PCR, and whole-cell patch recording. The 5-HT 2C receptor was G␣ q -coupled to PLC activation and hydrolysis of plasma membrane phosphatidylinositol bisphosphate to directly inhibit GIRK channel activity. Coapplication of the two agonists at their EC 50 concentrations (DOI, 20 M, and E 2 , 50 nM) produced additive effects. Although there was a significant gender difference in the effects of E 2 on baclofen responses, there was no gender difference in 5-HT 2C receptor-mediated effects. Finally, both DOI and estrogen (intracerebroventricular) inhibited feeding in ovariectomized female mice. Therefore, the G␣ q signaling pathways of the mER and 5-HT 2C receptors may converge to enhance synaptic efficacy in brain circuits that are critical for maintaining homeostatic functions.The hypothalamus is a key central nervous system center for controlling many homeostatic processes, and hypothalamic POMC neurons are critical neurons in these hypothalamic circuits (Elmquist et al., 1999;Cone, 2005;Gropp et al.,

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Assessment of a small molecule melanocortin-4 receptor-specific agonist on energy homeostasis

Cited by 29 publications

References 25 publications

Functional Selectivity of Melanocortin 4 Receptor Peptide and Nonpeptide Agonists: Evidence for Ligand-Specific Conformational States

Functional Selectivity of Melanocortin 4 Receptor Peptide and Nonpeptide Agonists: Evidence for Ligand-Specific Conformational States

Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity

Serotonin 5-Hydroxytryptamine_2CReceptor Signaling in Hypothalamic Proopiomelanocortin Neurons: Role in Energy Homeostasis in Females

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Assessment of a small molecule melanocortin-4 receptor-specific agonist on energy homeostasis

Cited by 29 publications

References 25 publications

Functional Selectivity of Melanocortin 4 Receptor Peptide and Nonpeptide Agonists: Evidence for Ligand-Specific Conformational States

Functional Selectivity of Melanocortin 4 Receptor Peptide and Nonpeptide Agonists: Evidence for Ligand-Specific Conformational States

Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity

Serotonin 5-Hydroxytryptamine2CReceptor Signaling in Hypothalamic Proopiomelanocortin Neurons: Role in Energy Homeostasis in Females

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Serotonin 5-Hydroxytryptamine_2CReceptor Signaling in Hypothalamic Proopiomelanocortin Neurons: Role in Energy Homeostasis in Females