The rostral ventromedial medulla （RVM） is a prominent component of the descending modulatory system involved in the control of spinal nociceptive transmission. In the current study, we investigated melanocortin-4 re...The rostral ventromedial medulla （RVM） is a prominent component of the descending modulatory system involved in the control of spinal nociceptive transmission. In the current study, we investigated melanocortin-4 receptor （MC4R） expression in the RVM, where the neurons involved in modulation of nociception reside. Using a line of mice expressing green fluorescent protein （GFP） under the control of the MC4R promoter, we found a large number of GFP-positive neurons in the RVM [nucleus raphe magnus （NRM） and nucleus gigantocellularis pars a （NGCa）]. Fluorescence immunohisto- chemistry revealed that approximately 10% of MC4R-GFP-positive neurons coexpressed tyrosine hydroxylase, indicating that they were catecholaminergic, whereas 50%-75% of those coexpressed tryp- tophan hydroxylase, indicating that they were serotonergic. Our findings support the hypothesis that MC4R signaling in RVM may modulate the activity of serotonergic sympathetic outflow sensitive to nociceptive signals, and that MC4R signaling in RVM may contribute to the descending modulation of nociceptive transmission.展开更多
Objective To investigate how F261S mutation identified from Chinese obese patients affects the function of melanocorfin 4 receptor (MC4R) and to analyze the obesity-related phenotypes in subjects carrying the F261S mu...Objective To investigate how F261S mutation identified from Chinese obese patients affects the function of melanocorfin 4 receptor (MC4R) and to analyze the obesity-related phenotypes in subjects carrying the F261S mutation. Methods F261S mutant of MC4R was generated by site-directed mutagenesis. Plasmids encoding wild-type or F261S mutant of MC4R were transfected into HEK293 and COS-7 cells to examine their functional characteristics. Signaling properties of F261S MC4R were assessed by measuring intracellular cAMP levels in response to α-MSH stimulation. Cell surface expression of F261S MC4R was compared with that of wild-type MC4R. Clinical examinations were performed in subjects carrying F261S mutation and in non-mutated controls. Results The a-MSH-stimulated reporter gene activity was significantly reduced in cells expressing F261S MC4R, with a maximal response equal to 57% of wild-type MC4R. The F261S mutation also led to a significant change in the EC50 value compared with the wild-type receptor (P〈0.01). Immunofluorescent assay revealed a marked reduction in plasma membrane localization of the MC4R in cells expressing the F261S mutant receptor. The resting metabolic rate and fat composition of the mutant carriers were not significantly different from those of the non-mutated obese controls. Conclusions The decreased response to α-MSH due to the intracellular retention of MC4R may cause early-onset obesity in the F261S pedigree of Chinese.展开更多
基金supported by grants from National Natural Science Foundation of China(No.81071307,No.81271766,and No.81673964)Special Fund of Fundamental Scientific Research Business Expense for Higher School of Central Government(No.2012TS060)
文摘The rostral ventromedial medulla （RVM） is a prominent component of the descending modulatory system involved in the control of spinal nociceptive transmission. In the current study, we investigated melanocortin-4 receptor （MC4R） expression in the RVM, where the neurons involved in modulation of nociception reside. Using a line of mice expressing green fluorescent protein （GFP） under the control of the MC4R promoter, we found a large number of GFP-positive neurons in the RVM [nucleus raphe magnus （NRM） and nucleus gigantocellularis pars a （NGCa）]. Fluorescence immunohisto- chemistry revealed that approximately 10% of MC4R-GFP-positive neurons coexpressed tyrosine hydroxylase, indicating that they were catecholaminergic, whereas 50%-75% of those coexpressed tryp- tophan hydroxylase, indicating that they were serotonergic. Our findings support the hypothesis that MC4R signaling in RVM may modulate the activity of serotonergic sympathetic outflow sensitive to nociceptive signals, and that MC4R signaling in RVM may contribute to the descending modulation of nociceptive transmission.
基金the National Natural Science Foundation of China (30470814 to Wei-Ping JIA)
文摘Objective To investigate how F261S mutation identified from Chinese obese patients affects the function of melanocorfin 4 receptor (MC4R) and to analyze the obesity-related phenotypes in subjects carrying the F261S mutation. Methods F261S mutant of MC4R was generated by site-directed mutagenesis. Plasmids encoding wild-type or F261S mutant of MC4R were transfected into HEK293 and COS-7 cells to examine their functional characteristics. Signaling properties of F261S MC4R were assessed by measuring intracellular cAMP levels in response to α-MSH stimulation. Cell surface expression of F261S MC4R was compared with that of wild-type MC4R. Clinical examinations were performed in subjects carrying F261S mutation and in non-mutated controls. Results The a-MSH-stimulated reporter gene activity was significantly reduced in cells expressing F261S MC4R, with a maximal response equal to 57% of wild-type MC4R. The F261S mutation also led to a significant change in the EC50 value compared with the wild-type receptor (P〈0.01). Immunofluorescent assay revealed a marked reduction in plasma membrane localization of the MC4R in cells expressing the F261S mutant receptor. The resting metabolic rate and fat composition of the mutant carriers were not significantly different from those of the non-mutated obese controls. Conclusions The decreased response to α-MSH due to the intracellular retention of MC4R may cause early-onset obesity in the F261S pedigree of Chinese.
