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 Gi 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 [125I]iodocyanopindolol, also occurred, and was concentration- and time-dependent. Maximum down-regulation of 40% occurred after 20 hr of exposure to 10 microM 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.
Pleus
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Department of Pharmacology, University of Nebraska Medical Center, Omaha.
Bylund
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D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects; D020120:Iodocyanopindolol; D007668:Kidney / Q000187:drug effects*; D009893:Opossums; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology*
D011985:Receptors, Serotonin; D005576:Colforsin; D012701:Serotonin; D020120:Iodocyanopindolol; D010869:Pindolol; D000242:Cyclic AMP