title: Beta 2-adrenoceptor agonist-induced down-regulation after short-term exposure.
abstract: We examined the effect of duration of beta 2-adrenergic receptor (beta 2AR) occupancy by isoproterenol on specific binding of 125I-lodocyanopindolol (125I-ICYP) in membranes from rat L6 myoblasts. Ten minute exposure caused a time-and concentration-dependent maximal decrease in 125I-ICYP binding 24 hours after exposure equal to that following continuous exposure (p < 0.05). Low temperature, concanavalin A, H89 and ICl 118,551 blocked the decline in 125I-ICYP binding during the first hour following exposure probably representing receptor sequestration to a compartment or change to a form incapable of ligand binding. Compared to controls, receptor binding 4 and 24 hours following exposure was reduced 56 +/- 8.7% and 72 +/- 8.8%, respectively (p < 0.05), and was blocked by ICl 118,551 but not CGP12177. Isoproterenol-induced, but not forskolin-stimulated, cAMP accumulation was reduced 35% 24 hours following exposure (p < 0.05). 125I-ICYP binding in intact L6 cells 4 and 24 hours after exposure were respectively 56 +/- 8.9 and 61 +/- 13% of controls (p < 0.05). Following agonist exposure, CHO cell membranes expressing human beta 2ARs exhibited 125I-ICYP binding 85 +/- 2.0% and 6 +/- 2.8% of control values 4 and 24 hours, respectively (p < 0.05). A model predicting that full occupation of the beta 2AR activates receptor degradation explains our results that agonist-induced down-regulation of beta 2AR does not require continuous presence of the agonist.
authors.affiliation: Department of Pediatrics, Le Bonheur Children's Medical Center, Memphis, TN 38103, USA.
authors.forename: A O
authors.initials: AO
authors.lastname: Hardin
authors.forename: J J
authors.initials: JJ
authors.lastname: Lima
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000502:physiology; D006224:Cricetinae; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007457:Iodine Radioisotopes; D020120:Iodocyanopindolol / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000502:physiology*; D011485:Protein Binding; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D013997:Time Factors
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D007457:Iodine Radioisotopes; D011943:Receptors, Adrenergic, beta; D020120:Iodocyanopindolol; D007545:Isoproterenol