The serotonin 5-HT 2A , 5-HT 2B , and 5-HT 2C G protein-coupled receptors signal primarily through Gα q to activate phospholipase C (PLC) and formation of inositol phosphates (IP) and diacylglycerol. The human 5-HT 2C receptor, expressed exclusively in the central nervous system, is involved in several physiological and psychological processes. Development of 5-HT 2C agonists that do not also activate 5-HT 2A or 5-HT 2B receptors is challenging because transmembrane domain identity is about 75% among 5-HT 2 subtypes. This paper reports 5-HT 2 receptor affinity and function of (1R,3S)-(−)-
Purpose: To compare the binding and agonistic activity of Acthar V R Gel and synthetic melanocortin receptor (MCR) agonists and examine how the activity of select agonists affects the in vivo production of corticosterone. Materials and Methods: In vitro binding was determined using concentration-dependent displacement of the ligand [ 125 I]Nle 4 , D-Phe 7-a-melanocyte-stimulating hormone (a-MSH) on cells expressing MC1R, MC3R, MC4R, or MC5R. Functional activity was determined using a time-resolved fluorescence cyclic adenosine monophosphate (cAMP) assay in cells expressing MC1R, MC2R, MC3R, MC4R, or MC5R. In vivo corticosterone analyses were performed by measuring plasma corticosterone levels in Sprague Dawley rats. Results: Acthar Gel and synthetic MCR agonists exhibited the highest binding at MC1R, lowest binding at MC5R, and moderate binding at MC3R and MC4R. Acthar Gel stimulated the production of cAMP in all 5 MCR-expressing cell lines, with MC2R displaying the lowest level of full agonist activity, 3-, 6.6-, and 10-fold lower than MC1R, MC3R, and MC4R, respectively. Acthar Gel was a partial agonist at MC5R. The synthetic MCR agonists induced full activity at all 5 MCRs, with the exception of a-MSH having no activity at MC2R. Acthar Gel treatment had less of an impact on in vivo production of corticosterone compared with synthetic ACTH 1-24 depot. Conclusions: Acthar Gel bound to and activated each MCR tested in this study, with partial agonist activity at MC5R and the lowest level of full agonist activity at MC2R, which distinguished it from synthetic MCR agonists. The minimal activity of Acthar Gel at MC2R corresponded to lower endogenous corticosteroid production.
The present study was to evaluate the effect of melatonin (MT) and EA on the cytotoxic activity of natural killer (NK) cells, the dynamic changes of the induction of interleukin-2(IL-2) and the content of POMC-derived peptides, beta-endorphins (betaE) and ACTH in spleen lymphocytes and in plasma of traumatic rats. The results showed that intraperitioneal (i.p.) injection of MT was able to recover the lower levels of NK cell activity and the induction of IL-2 production; MT could also decrease the higher betaE and ACTH levels induced by trauma in spleen lymphocytes and plasma. EA needling of Zusanli (St.36) and Lanwei (Extra.37) points obviously improved the immunosuppression produced by trauma and antagonized the elevation of betaE and ACTH contents induced by trauma stress in spleen lymphocytes and plasma. MT + EA could further modulate the depressed immune function, and there was a significant difference compared with MT (i.p.) or EA alone. MT + EA group further decreased the betaE and ACTH contents in immune cells and plasma. Yet, the mechanisms of the attenuation of MT and EA on immunosuppression induced by trauma need further study.
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