European Journal of Pharmacology 2004-09-13

Regulation of serotonin 5-HT2C receptors by chronic ligand exposure.

Mark G Devlin, Nicola J Smith, Olivia M Ryan, Elizabeth Guida, Patrick M Sexton, Arthur Christopoulos

Index: Eur. J. Pharmacol. 498(1-3) , 59-69, (2004)

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Abstract

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.