ABSTRACT
Inasmuch as the neurohormone melatonin is synthetically derived from serotonin (5-HT), a close interrelationship between both has long been suspected. The present study reveals a hitherto unrecognized cross-talk mediated via physical association of melatonin MT2 and 5-HT2C receptors into functional heteromers. This is of particular interest in light of the "synergistic" melatonin agonist/5-HT2C antagonist profile of the novel antidepressant agomelatine. A suite of co-immunoprecipitation, bioluminescence resonance energy transfer, and pharmacological techniques was exploited to demonstrate formation of functional MT2 and 5-HT2C receptor heteromers both in transfected cells and in human cortex and hippocampus. MT2/5-HT2C heteromers amplified the 5-HT-mediated Gq/phospholipase C response and triggered melatonin-induced unidirectional transactivation of the 5-HT2C protomer of MT2/5-HT2C heteromers. Pharmacological studies revealed distinct functional properties for agomelatine, which shows "biased signaling." These observations demonstrate the existence of functionally unique MT2/5-HT2C heteromers and suggest that the antidepressant agomelatine has a distinctive profile at these sites potentially involved in its therapeutic effects on major depression and generalized anxiety disorder. Finally, MT2/5-HT2C heteromers provide a new strategy for the discovery of novel agents for the treatment of psychiatric disorders.
Subject(s)
Melatonin/metabolism , Protein Multimerization , Receptor, Melatonin, MT2/chemistry , Receptor, Serotonin, 5-HT2C/chemistry , Serotonin/metabolism , Signal Transduction , Acetamides/pharmacology , Arrestins/metabolism , Drug Synergism , Gene Expression Regulation/drug effects , HEK293 Cells , HeLa Cells , Humans , Melatonin/pharmacology , Protein Multimerization/drug effects , Protein Structure, Quaternary , Protein Transport/drug effects , Receptor, Melatonin, MT1/metabolism , Receptor, Melatonin, MT2/genetics , Receptor, Melatonin, MT2/metabolism , Receptor, Serotonin, 5-HT2C/genetics , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin/pharmacology , Signal Transduction/drug effects , Transcriptional Activation/drug effects , Transcriptional Activation/genetics , Type C Phospholipases/metabolism , beta-ArrestinsSubject(s)
Immunosuppressive Agents/pharmacology , Nicotine/pharmacology , Nitric Oxide/physiology , Surgical Flaps/blood supply , Tacrolimus/pharmacology , Transplantation Conditioning/methods , Animals , Dose-Response Relationship, Drug , Graft Survival/drug effects , Male , Rats , Skin TransplantationABSTRACT
Cannabinoids are psychoactive compounds with many pharmacological properties such as analgesia, sedation and catalepsy most of which are mediated by cannabinoid CB1 receptors. In the present study, we evaluated whether the ovarian sex hormones are involved in the cannabinoid-induced catalepsy and analgesia in ovariectomized female mice. Female NMRI mice (weighing 25-30 g) were divided into 3 main groups: unoperated, sham-operated and ovariectomized. Both the catalepsy and analgesia induced by different doses of the synthetic cannabinoid WIN 55,212-2 (2 and 4 mg/kg, i.p.) were examined in the groups in the presence or absence of the cannabinoid CB1 antagonist AM251 (0.5 mg/kg). We also evaluated effects of estradiol valerate (10 mg/kg) and progesterone (25 mg/kg) on catalepsy and analgesia induced by WIN 55,212-2 in ovariectomized mice. The antinociceptive effect of WIN 55,212-2 was significantly (P<0.01) enhanced in ovariectomized mice, which was prevented by pretreatment with estradiol but not by progesterone. There was no significant difference in the cannabinoid-induced catalepsy between control and ovariectomized mice. However, pretreatment with progesterone but not estradiol potentiated the cataleptic effect of low dose of WIN 55,212-2 (2 mg/kg) in ovariectomized mice (P<0.01). The present data demonstrated for the first time that ovarian sex steroids could modulate both cannabinoid-induced catalepsy and analgesia in female ovariectomized mice.