Differences between human wild-type and C23S variant 5-HT2C receptors in inverse agonist-induced resensitization

The aim of this study was to analyze functional properties of the naturally occurring c23s variant of the human 5-ht2c receptor. in hek293 cells transiently expressing the unedited forms of the variant receptor (vr) or the wild-type receptor (wtr),surface expression was determined by [ 3h]mesulergine binding to membrane fragments. function was examined by an aequorin luminescence-based ca2+ assay. surface expression of the vr was 116% of that of the wtr. the 5-ht-induced increase in cytosolic ca2+ ([ca2+]i),and its inhibition by the inverse agonist sb 206553 did not differ between vr- or wtr-expressing cells. preexposure of vr- or wtr-expressing cells to 0.5 μm 5-ht (3 min-4.5 h) led to a practically identical time course and extent in the reduction of the 5-ht-induced increase in [ca2+]i. in contrast,prolonged preexposure to the inverse agonist sb 206553 (1 μm) elevated the 5-ht-induced increase in [ca2+]i for both isoreceptors. a preexposure time of 4.5 h was necessary to significantly elevate the ca2+ response of the wtr,but the vr produced this elevation within 1 h with virtually no further effect after 4.5 h of preexposure. in conclusion,prolonged preexposure to 5-ht caused equally rapid and strong desensitization of both isoreceptors. the different time course of sb 206553-induced resensitization of the two isoreceptors might be therapeutically relevant for drugs exhibiting inverse agonist properties at 5-ht2c receptors,such as atypical antipsychotics and certain antidepressants. copyright © 2011 by institute of pharmacology polish academy of sciences.