Agonist-promoted down-regulation and functional desensitization in two naturally occurring variants of the human serotonin1A receptor.
We recently reported two naturally occurring polymorphisms of the human serotonin1A (5-HT1A) 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-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 mumol/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 mumol/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.
Rotondo
A
A
Section of Molecular Genetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland 20852, USA.
Nielsen
D A
DA
Nakhai
B
B
Hulihan-Giblin
B
B
Bolos
A
A
Goldman
D
D
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D015536:Down-Regulation / Q000502:physiology; D006801:Humans; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin