title: Differences between human wild-type and C23S variant 5-HT2C receptors in inverse agonist-induced resensitization.
abstract: 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.
authors: Institute of Pharmacology and Toxicology, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors: Jutta
authors: J
authors: Walstab
authors: Folkert
authors: F
authors: Steinhagen
authors: Michael
authors: M
authors: Brüss
authors: Manfred
authors: M
authors: Göthert
authors: Heinz
authors: H
authors: Bönisch
mesh_terms: D000328:Adult; D000331:Aequorin / Q000737:chemistry; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism*; D018076:DNA, Complementary / Q000737:chemistry; D054314:Drug Inverse Agonism; D004873:Ergolines / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008163:Luminescent Measurements / Q000379:methods; D011485:Protein Binding; D011725:Pyridines / Q000494:pharmacology*; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000008:administration & dosage / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology; D013997:Time Factors
chemical_list: D018076:DNA, Complementary; D004873:Ergolines; D007211:Indoles; D011725:Pyridines; D044405:Receptor, Serotonin, 5-HT2C; D012702:Serotonin Antagonists; D012701:Serotonin; D000331:Aequorin; C094868:SB 206553; C031649:mesulergine; D002118:Calcium