Pharmacology of polymorphic variants of the human 5-HT1A receptor.
The 5-HT1A receptor is a critical mediator of serotonergic (5-HT) function. We have identified 13 potential single nucleotide polymorphisms resulting in amino acid changes throughout the human 5-HT1A receptor. The pharmacological profiles of these 13 polymorphic variants were then characterized using a high-throughput assay based on ligand-dependent transformation of NIH/3T3 cells. The majority of the polymorphic variants displayed wild-type pharmacological profiles in response to a panel of well-established agonists at the 5-HT1A receptor. However, the A50V polymorphic variant, which had an alanine to valine substitution in transmembrane 1, exhibited a loss of detectable response to 5-HT. Interestingly, all other agonists tested, including buspirone, lisuride, and (+)8-OH-DPAT, exhibited efficacies similar to that of the wild-type receptor. The competitive antagonist, methiothepin, also displayed a 19-fold decrease in potency at the A50V variant receptor. However, both 5-HT and methiothepin were able to compete for [3H]WAY-100635 binding to the A50V variant with affinities similar to the wild-type receptor. Moreover, the Bmax of [3H]WAY-100635 binding was 14-fold lower for the A50V variant than for the wild-type receptor. Thus, the A50V receptor variant exhibited ligand-specific functional alterations in addition to lower expression levels. These data suggest a previously unappreciated role for transmembrane 1 in mediating 5-HT response at the 5-HT1A receptor. Furthermore, individuals that potentially harbor the A50V polymorphism might display aberrant affective behaviors and altered responses to drugs targeting the 5-HT1A receptor.
Del Tredici
Andria L
AL
ACADIA Pharmaceuticals, 3911 Sorrento Valley Blvd, San Diego, CA 92121-1402, USA. alee@acadia-pharm.com
Schiffer
Hans H
HH
Burstein
Ethan S
ES
Lameh
Jelveh
J
Mohell
Nina
N
Hacksell
Uli
U
Brann
Mark R
MR
Weiner
David M
DM
D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D051379:Mice; D016297:Mutagenesis, Site-Directed; D011110:Polymorphism, Genetic; D011869:Radioligand Assay; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D013462:Sulfur Radioisotopes
D012702:Serotonin Antagonists; D013462:Sulfur Radioisotopes; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D016244:Guanosine 5'-O-(3-Thiotriphosphate)