Impairment of signal transduction in response to stimulation of the naturally occurring Pro279Leu variant of the h5-HT7(a) receptor.
The aim of this study, performed in stably transfected HEK293 cells, was to investigate whether expression of the naturally occurring Pro279Leu variant of the h5-HT7(a) receptor (located in the third intracellular loop) is associated with changes in the pharmacological properties and/or second messenger formation compared to the wild-type receptor. Radioligand binding of [3H]5-carboxamidotryptamine ([3H]5-CT) to membranes and stimulation of [3H]cAMP formation in whole cells evoked by 5-HT receptor agonists were determined. Maximum binding (B(max)) to, and affinity (K(D)) of [3H]5-CT for, the variant receptor and the wild-type receptor were equal. All agonists and antagonists investigated exhibited no differences in affinity between the variant receptor and the wild-type receptor. However, the intrinsic activity of the 5-HT receptor agonists 5-HT, 5-CT, RU24969 and 8-OH-DPAT in stimulating [3H]cAMP accumulation in the cells expressing the Pro279Leu variant was almost abolished and their potency was 2.9-4.3-fold lower. Despite its affinity for both receptor isoforms, sumatriptan did not stimulate the accumulation of cAMP. In individuals expressing the Pro279Leu variant of the h5-HT7(a) receptor, a considerable attenuation of its function may be predicted. This may have relevance for the action of new classes of drugs which affect circadian rhythm or psychiatric diseases, such as schizophrenia.
Kiel
Sibylle
S
Institute of Pharmacology and Toxicology, University of Bonn, Reuterstrasse 2b, D-53113 Bonn, Germany.
Bönisch
Heinz
H
Brüss
Michael
M
Göthert
Manfred
M
D001667:Binding, Competitive; D002462:Cell Membrane; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007930:Leucine / Q000737:chemistry; D008024:Ligands; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000378:metabolism*; D015290:Second Messenger Systems; D012701:Serotonin / Q000031:analogs & derivatives* / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
D008024:Ligands; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C104425:serotonin 7 receptor; D012701:Serotonin; C047087:5-carboxamidotryptamine; D011392:Proline; D000242:Cyclic AMP; D007930:Leucine