title: {Beta}-blocker drugs mediate calcium signaling in native central nervous system neurons by {beta}-arrestin-biased agonism.
abstract: G protein-coupled receptors (GPCRs), the largest family of signaling receptors expressed in the CNS, mediate the neuropsychiatric effects of a diverse range of clinically relevant drugs. It is increasingly clear that GPCRs can activate distinct G protein-dependent and -independent transduction pathway(s), and that certain drugs differ in the ability to regulate distinct signaling mechanisms linked to the same receptors. A fundamental question in neuropharmacology is whether such "biased agonism" occurs in physiologically relevant neurons and with endogenous receptors. Here we show that propranolol and carvedilol, two β-blocker drugs that inhibit β-adrenergic signaling via heterotrimeric G proteins, function in hippocampal pyramidal neurons as potent and selective activators of an alternate receptor-linked calcium signaling pathway mediated by β-arrestin-2 and ERK1/2. Our results support the emerging view of β-arrestin-biased agonism as a significant mechanism of drug action and do so in CNS-derived neurons expressing only native receptors.
authors.affiliation: Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Anastassios V
authors.initials: AV
authors.lastname: Tzingounis
authors.forename: Mark
authors.initials: M
authors.lastname: von Zastrow
authors.forename: Guillermo A
authors.initials: GA
authors.lastname: Yudowski
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D019390:Arrestins; D020013:Calcium Signaling / Q000187:drug effects*; D002227:Carbazoles / Q000494:pharmacology; D000077261:Carvedilol; D002490:Central Nervous System / Q000166:cytology; D006624:Hippocampus / Q000166:cytology; D048052:Mitogen-Activated Protein Kinase 3; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D043562:Receptors, G-Protein-Coupled; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: D000319:Adrenergic beta-Antagonists; C000605257:Arrb2 protein, rat; D019390:Arrestins; D002227:Carbazoles; D011412:Propanolamines; D043562:Receptors, G-Protein-Coupled; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D000077261:Carvedilol; D011433:Propranolol; D048052:Mitogen-Activated Protein Kinase 3