Abstract
We recently reported two naturally occurring polymorphisms of the human serotonin1A (5-HT1A) receptor: glycine22→serine (Ser22) and isoleucine28→valine (Val28) in the putative amino-terminal domain of the receptor. To investigate the regulatory properties of these variants, the wild type (WT) and variant 5-HT1A 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-HT1A agonists and antagonists demonstrated similar pharmacological profiles. Receptor agonist-promoted down-regulation was tested by exposure to 100 μmol/L 8-OH-DPAT. After 24-h exposure, 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 ± 5.1% 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.
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Acknowledgements
We thank Gary L. Jenkins and Longina Aktar for their excellent technical assistance, Dr. Chun Mak for very helpful suggestions, and Dr. D. Sibley for his critical reading of the manuscript. A. Rotondo was in part supported by the IDEA ASSOCIATION (Institute for the Treatment and Prevention of Depression and Anxiety), via Statuto, 8 - 20121 Milan, Italy.
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Rotondo, A., Nielsen, D., Nakhai, B. et al. Agonist-Promoted Down-Regulation and Functional Desensitization in Two Naturally Occurring Variants of the Human Serotonin1A Receptor. Neuropsychopharmacol 17, 18–26 (1997). https://doi.org/10.1016/S0893-133X(97)00021-3
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DOI: https://doi.org/10.1016/S0893-133X(97)00021-3
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