A single mutation in the 5-HT4 receptor (5-HT4-R D100(3.32)A) generates a Gs-coupled receptor activated exclusively by synthetic ligands (RASSL).
To better understand G-protein-coupled receptor (GPCRs) signaling, cellular and animal physiology, as well as gene therapy, a new tool has recently been proposed. It consists of GPCR mutants that are insensitive to endogenous ligands but sensitive to synthetic ligands. These GPCRs are called receptor activated solely by synthetic ligands (RASSL). Only two examples of such engineered receptors have been described so far: one G(i)-coupled (opioid receptors) and one G(s)-coupled (beta(2)-adrenergic receptors). Here, we describe the first RASSL related to serotonin receptors (D100(3.32)A G(s)-coupled 5-HT(4) receptor or 5-HT(4)-RASSL). 5-HT(4)-RASSL is generated by a single mutation, is totally insensitive to serotonin (5-HT), and still responds to synthetic ligands. These ligands have affinities in the range of nanomolar concentrations for the mutant receptor and exhibit full efficacy. More interestingly, two synthetic ligands behave as antagonists on the wild type but as agonists on the 5-HT(4)-RASSL.
Claeysen
Sylvie
S
Centre National de la Recherche Scientifique, UPR 9023, 141 rue de la Cardonille, 34094 Montpellier, Cedex 5, France.
Joubert
Lara
L
Sebben
Michèle
M
Bockaert
Joël
J
Dumuis
Aline
A
D000818:Animals; D019556:COS Cells; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism*; D015316:Genetic Therapy; D008024:Ligands; D009154:Mutation; D011956:Receptors, Cell Surface / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D044422:Receptors, Serotonin, 5-HT4; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D008024:Ligands; D011956:Receptors, Cell Surface; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4; D019205:GTP-Binding Protein alpha Subunits, Gs