Regulation of serotonin 5-HT2C receptors by chronic ligand exposure.
The effect of ligand pretreatment on human 5-hydroxytryptamine2C (5-HT2C) receptors was examined in CHO cells expressing high (CHO-1C7; 67+/-3 pmol/mg) or low (CHO-1C19; 72+/-10 fmol/mg) levels of the receptor. Seventy-two hours pretreatment of CHO-1C7 cells with various ligands did not affect receptor expression. Pretreatment with inverse agonists enhanced 5-HT-mediated inositol phosphate accumulation with no change in constitutive receptor activity. The enhanced agonist responsiveness was inversely correlated with the intrinsic activity of the pretreatment ligand. Seventy-two hours of pretreatment with the weak agonist, 5-methoxygramine, caused an elevation in constitutive activity but no alteration in 5-HT-mediated signaling. In CHO-1C19 cells, 24 but not 72 h of pretreatment with the inverse agonist mianserin enhanced 5-HT-mediated signaling, with no effect on basal signaling; pretreatment with 5-methoxygramine had no significant effect. These findings highlight differences in the pattern of chronic regulation of 5HT2C receptor signaling between high and low receptor expression levels in a common cellular background.
Devlin
Mark G
MG
Department of Pharmacology, University of Melbourne, Parkville, 3010 Victoria, Australia.
Smith
Nicola J
NJ
Ryan
Olivia M
OM
Guida
Elizabeth
E
Sexton
Patrick M
PM
Christopoulos
Arthur
A
D000465:Algorithms; D000704:Analysis of Variance; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002746:Chlorpromazine / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004873:Ergolines / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007215:Indophenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D008090:Lisuride / Q000494:pharmacology; D008803:Mianserin / Q000494:pharmacology; D011869:Radioligand Assay; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics / Q000378:metabolism*; D016713:Ritanserin / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014316:Tritium; D014363:Tryptamines / Q000494:pharmacology
D004873:Ergolines; D007211:Indoles; D007295:Inositol Phosphates; D008024:Ligands; D044405:Receptor, Serotonin, 5-HT2C; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C113896:dimethoxy-4-indophenyl-2-aminopropane; D014316:Tritium; D016713:Ritanserin; C008398:methoxygramine; D008803:Mianserin; D012701:Serotonin; D007215:Indophenol; D008090:Lisuride; C031649:mesulergine; D002746:Chlorpromazine