His452Tyr polymorphism in the human 5-HT2A receptor destabilizes the signaling conformation.

Naturally occurring variation within the human 5-HT(2A) receptor results in an amino acid substitution in the carboxyl terminus of the receptor. This single nucleotide polymorphism (SNP), encoding a His452Tyr substitution, occurs at a frequency of 9% in the general population. It is noteworthy that this SNP has been linked to attention deficit hyperactivity disorder and has been associated with schizophrenic patients that do not respond to treatment with clozapine. To evaluate functional consequences of this SNP, agonist-stimulated signaling was investigated in NIH3T3 cells stably expressing either wild-type or 452Tyr variant receptors. The 452Tyr variant of the 5-HT(2a) receptor had reduced ability to activate phospholipases C and D, suggesting that signaling through both G(q) and G(13) pathways is hindered. This conclusion was supported by assays of G protein coupling, which documented a loss of agonist-induced high affinity binding and a decreased turnover of guanosine 5'-O-(3-[(35)S]thio)triphosphate after agonist stimulation. Kinetic analysis of time-course data revealed an altered desensitization phenotype, resulting in a blunted signal downstream of receptor activation. This diminished signaling implies that the His452Tyr variant receptor alters physiological responses, possibly contributing to psychiatric disease.