The cloned human 5-HT1E receptor couples to inhibition and activation of adenylyl cyclase via two distinct pathways in transfected BS-C-1 cells.
The pharmacological profile of coupling of the cloned human serotonin [5-hydroxytryptamine] (5-HT)1E receptors to second messengers was studied in African green monkey kidney cells (BS-C-1). At low concentrations (0.1-100 nM), 5-HT inhibited forskolin-stimulated cAMP accumulation (FSCA) by up to 90% whereas at higher concentrations it potentiated FSCA; potentiation was dependent on receptor density. Pretreatment of cells with pertussis toxin (PTx) or cholera toxin (CTx) eliminated agonist-induced inhibition and potentiation of FSCA, respectively. The potentiation of FSCA was not due to activation of phospholipase C and/or phospholipase A2 since 5-HT had no effect on inositol phosphate release, intracellular Ca2+ mobilization or arachidonic acid mobilization; neither was it affected by pretreatment with the nonselective phospholipase A2 inhibitor, quinacrine, or by the removal of extracellular Ca2+. The pharmacological profiles of the 5-HT1E receptor-mediated inhibition and potentiation of FSCA were very similar, although agonists displayed higher affinity for the former. These results indicate that the human 5-HT1E receptors can potentially couple, with similar pharmacological profiles, to multiple effector pathways. However, the potency and intrinsic activity of the compounds eliciting these responses can differ significantly, depending on the receptor density and the effector pathway studied.
Adham
N
N
Synaptic Pharmaceutical Corporation, Paramus, N.J. 07652.
Vaysse
P J
PJ
Weinshank
R L
RL
Branchek
T A
TA
D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002772:Cholera Toxin / Q000494:pharmacology; D003001:Cloning, Molecular; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D019204:GTP-Binding Proteins / Q000378:metabolism; D000882:Haplorhini; D006801:Humans; D008719:Methiothepin / Q000494:pharmacology; D037342:Pertussis Toxin; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism*; D015290:Second Messenger Systems / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D011985:Receptors, Serotonin; D010566:Virulence Factors, Bordetella; D005576:Colforsin; D008719:Methiothepin; D002772:Cholera Toxin; D000242:Cyclic AMP; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases