title: Agonist-directed desensitization of the β2-adrenergic receptor.
abstract: The β(2)-adrenergic receptor (β(2)AR) agonists with reduced tachyphylaxis may offer new therapeutic agents with improved tolerance profile. However, receptor desensitization assays are often inferred at the single signaling molecule level, thus ligand-directed desensitization is poorly understood. Here we report a label-free biosensor whole cell assay with microfluidics to determine ligand-directed desensitization of the β(2)AR. Together with mechanistic deconvolution using small molecule inhibitors, the receptor desensitization and resensitization patterns under the short-term agonist exposure manifested the long-acting agonism of salmeterol, and differentiated the mechanisms of agonist-directed desensitization between a full agonist epinephrine and a partial agonist pindolol. This study reveals the cellular mechanisms of agonist-selective β(2)AR desensitization at the whole cell level.
authors.affiliation: Biochemical Technologies, Science and Technology Division, Corning Inc., Corning, New York, United States of America.
authors.forename: Vasiliy
authors.initials: V
authors.lastname: Goral
authors.forename: Yan
authors.initials: Y
authors.lastname: Jin
authors.forename: Haiyan
authors.initials: H
authors.lastname: Sun
authors.forename: Ann M
authors.initials: AM
authors.lastname: Ferrie
authors.forename: Qi
authors.initials: Q
authors.lastname: Wu
authors.forename: Ye
authors.initials: Y
authors.lastname: Fang
mesh_terms: D000318:Adrenergic beta-Agonists / Q000737:chemistry / Q000494:pharmacology*; D015374:Biosensing Techniques; D045744:Cell Line, Tumor; D004705:Endocytosis / Q000187:drug effects; D004837:Epinephrine / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008024:Ligands; D044085:Microfluidics; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D010869:Pindolol / Q000494:pharmacology; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000318:Adrenergic beta-Agonists; D008024:Ligands; D018343:Receptors, Adrenergic, beta-2; D010869:Pindolol; D048049:Extracellular Signal-Regulated MAP Kinases; D004837:Epinephrine