Agonist-promoted down-regulation and functional desensitization in two naturally occurring variants of the human serotonin(1A) receptor

We recently reported two naturally occurring polymorphisms of the human serotonin(1A) (5-HT(1A)) receptor: glycine22→serine (Ser22) and isoleucine28→valine (Val28) in the putative aminoterminal domain of the receptor. To investigate the regulatory properties of these variants, the wild type (WT) and variant 5-HT(1A) receptors were stably expressed in CHO-K1 cells. WT, Ser22, and Val28 displayed similar high-affinity binding to [3H]-8-OH-DPAT. Competition experiments with 5-HT(1A) agonists and antagonists demonstrated similar pharmacological profiles. Receptor agonist-promoted down-regulation was tested by exposure to 200 μmol/L 8-OH-DPAT. After 24-h exposture, WT and Val28 underwent 59.3 ± 3.9% and 59.5 ± 1.4% reduction in receptor density respectively, whereas the degree of down-regulation was significantly lower for Ser22 (21.4 ± 4.2%). Cell treatment for 24 h with 100 μmol/L 8-OH-DPAT reduced the 5-HT-induced inhibition of cAMP accumulation by 24.9 ± 5.2% for WT and 16.4 ± 0.8% for Val28, but only by 4.8 ± 3% for Ser22. We conclude that the Ser22 variant is capable of attenuating agonist-mediated receptor down-regulation and desensitization.