Partial agonist properties of rauwolscine and yohimbine for the inhibition of adenylyl cyclase by recombinant human 5-HT1A receptors.
Previous studies by another group have suggested that the alpha 2-adrenergic receptor antagonist rauwolscine may function as an agonist at the serotonin1A (5-HT1A) receptor expressed in human brain. To directly test that hypothesis, we transfected the human 5-HT1A receptor cDNA into CHO cells and examined the ability of rauwolscine and its isomer, yohimbine, to inhibit ligand binding of [3H]-(+/-)-8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT) and the activity of adenylyl cyclase in membranes derived from a single transformant that stably expresses approximately 225 fmol of 5-HT1A receptor/mg of membrane protein. Both ligands competitively antagonized the binding of [3H]8-OH-DPAT (Ki = 158 +/- 69 nM for rauwolscine and 690 +/- 223 nM for yohimbine), yielding shallow displacement curves consistent with agonist activity (Hill values = 0.69 +/- 0.2 for rauwolscine and 0.63 +/- 0.06 for yohimbine). Both ligands also inhibited forskolin-stimulated adenylyl cyclase activity in membranes derived from transfected (but not nontransfected) cells. For rauwolscine, the IC50 was 1.5 +/- 0.2 microM, and for yohimbine 4.6 +/- 1.0 microM, with activity ratios of 0.70 and 0.59, respectively, when compared to the full agonist serotonin. These studies demonstrated that rauwolscine and yohimbine are partial agonists for the human 5-HT1A receptor.
Department of Medicine (Nephrology and Cardiology), Duke University Medical Center, Durham, NC 27710.
J M
JM
Arthur
S J
SJ
Casañas
J R
JR
Raymond
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism; D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D011994:Recombinant Proteins / Q000378:metabolism; D012702:Serotonin Antagonists; D014162:Transfection; D015016:Yohimbine / Q000737:chemistry / Q000494:pharmacology*
D000067956:Adenylyl Cyclase Inhibitors; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D011994:Recombinant Proteins; D012702:Serotonin Antagonists; D015016:Yohimbine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin