The naturally occurring Arg219Leu variant of the human 5-HT1A receptor: impairment of signal transduction.
The present study in transfected HEK293 cells aimed to investigate whether the pharmacological and/or transductional properties of the naturally occurring Arg219Leu variant (VAR) in the third intracellular loop of the h5-HT1A receptor differ from those of the wild-type receptor. Binding of [3H]8-hydroxy-2-(di-n-propylamino)tetraline ([H]8-OH-DPAT) and of [35S]GTPgammaS to membranes, as well as inhibition of forskolin-stimulated [3H]cAMP formation by 5-HT receptor agonists in whole cells, were estimated. The VAR and wild-type h5-HT1A receptors were found to be expressed at virtually identical densities. The VAR and wild-type receptors did also not differ with respect to the potencies of 5-HT receptor agonists and antagonists in inhibiting [3H]8-OH-DPAT binding. The ability of 5-HT to stimulate [35S]GTPgammaS binding (a measure of G protein coupling) to the VAR receptor and of the agonists 5-HT, buspirone and urapidil to inhibit forskolin-stimulated cAMP accumulation in HEK293 cells expressing the VAR receptor was decreased by 60-90%. In conclusion, the Arg219Leu variation of the human 5-HT1A receptor does not change the binding properties, but is associated with a drastic impairment of signal transduction. In patients carrying this variation, disturbances of 5-HT1A receptor-mediated functions and diminished responses to drugs acting via this receptor may occur.
Brüss
Michael
M
Institute of Pharmacology and Toxicology, University of Bonn, Bonn, Germany. m.bruess@uni-bonn.de
Kostanian
Arevat
A
Bönisch
Heinz
H
Göthert
Manfred
M
D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001120:Arginine / Q000737:chemistry; D002065:Buspirone / Q000494:pharmacology; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D014644:Genetic Variation; D006801:Humans; D020128:Inhibitory Concentration 50; D007930:Leucine / Q000737:chemistry; D010597:Pharmacogenetics; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D015398:Signal Transduction; D014162:Transfection
D014151:Anti-Anxiety Agents; D010879:Piperazines; D012702:Serotonin Antagonists; D044282:Receptor, Serotonin, 5-HT1A; D005576:Colforsin; D001120:Arginine; C015568:urapidil; D000242:Cyclic AMP; D007930:Leucine; D002065:Buspirone