Differences between human wild-type and C23S variant 5-HT2C receptors in inverse agonist-induced resensitization
| Autor: | Heinz Bönisch, Jutta Walstab, Manfred Göthert, Folkert Steinhagen, Michael Brüss |
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| Rok vydání: | 2011 |
| Předmět: |
Adult
Serotonin medicine.medical_specialty DNA Complementary Indoles Time Factors Drug Inverse Agonism Pyridines Aequorin chemistry.chemical_element Calcium Pharmacology chemistry.chemical_compound Internal medicine Receptor Serotonin 5-HT2C medicine Humans Inverse agonist Ergolines Receptor 5-HT receptor Mesulergine SB-206553 Base Sequence biology Wild type General Medicine HEK293 Cells Endocrinology chemistry Luminescent Measurements biology.protein Serotonin Antagonists Protein Binding |
| Zdroj: | Pharmacological Reports. 63:45-53 |
| ISSN: | 1734-1140 |
| DOI: | 10.1016/s1734-1140(11)70397-8 |
| Popis: | The aim of this study was to analyze functional properties of the naturally occurring C23S variant of the human 5-HT 2C 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 [ 3 H]mesulergine binding to membrane fragments. Function was examined by an aequorin luminescence-based Ca 2+ assay. Surface expression of the VR was 116% of that of the WTR. The 5-HT-induced increase in cytosolic Ca 2+ ([Ca 2+ ] 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 [Ca 2+ ];. In contrast, prolonged preexposure to the inverse agonist SB 206553 (1 µM) elevated the 5-HT-induced increase in [Ca 2+ ] i for both isoreceptors. A preexposure time of 4.5 h was necessary to significantly elevate the Ca 2+ 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-HT 2C receptors, such as atypical antipsychotics and certain antidepressants. |
| Databáze: | OpenAIRE |
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