DESENSITIZATION AND DOWN-REGULATION OF THE 5-HYDROXYTRYPTAMINE1B RECEPTOR IN THE OPOSSUM KIDNEY-CELL LINE

In the opossum kidney cell line the 5-hydroxytryptamine (serotonin; 5-HT)1B receptor is negatively coupled to adenylyl cyclase via a G(i) protein. Preincubation of opossum kidney cell line cell monolayers with 5-HT resulted in 5-HT1B receptor-mediated desensitization expressed as a 4-fold rightward shift of the dose-response curve and a 10 to 29% decrease of maximal inhibition of forskolin-stimulated cyclic AMP production. These moderate decreases in potency and efficacy were concentration- and time-dependent. Maximal desensitization occurred with 3 hr of 5-HT preincubation. Preincubation with 5-HT caused no change in the potency or efficacy of alpha-2 adrenergic agonist-mediated inhibition of forskolin-stimulated cyclic AMP production. Therefore, the desensitization caused by 5-HT preincubation appears to be homologous. Down-regulation of the 5-HT1B receptor, assessed with the high affinity radioligand [I-125]iodocyanopindolol, also occurred, and was concentration- and time-dependent. Maximum down-regulation of 40% occurred after 20 hr of exposure to 10-mu-M 5-HT. These results demonstrate that, like other receptors coupled to the inhibition of adenylyl cyclase, exposure of 5-HT1B receptors to an agonist causes desensitization of the functional response followed by down-regulation of the receptor.