β-Blocker drugs mediate calcium signaling in native central nervous system neurons by β-arrestin–biased agonism
- 15 November 2010
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 107 (49), 21028-21033
- https://doi.org/10.1073/pnas.1004169107
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.Keywords
This publication has 31 references indexed in Scilit:
- Beyond extinction: erasing human fear responses and preventing the return of fearNature Neuroscience, 2009
- A unique mechanism of β-blocker action: Carvedilol stimulates β-arrestin signalingProceedings of the National Academy of Sciences of the United States of America, 2007
- Collateral efficacy in drug discovery: taking advantage of the good (allosteric) nature of 7TM receptorsTrends in Pharmacological Sciences, 2007
- Hippocalcin Gates the Calcium Activation of the Slow Afterhyperpolarization in Hippocampal Pyramidal CellsNeuron, 2007
- Cargo Regulates Clathrin-Coated Pit DynamicsCell, 2006
- Distinct Signaling Profiles of β1 and β2 Adrenergic Receptor Ligands toward Adenylyl Cyclase and Mitogen-Activated Protein Kinase Reveals the Pluridimensionality of EfficacyMolecular Pharmacology, 2006
- Distinct modes of regulated receptor insertion to the somatodendritic plasma membraneNature Neuroscience, 2006
- New Concepts in Drug Discovery: Collateral Efficacy and Permissive AntagonismNature Reviews Drug Discovery, 2005
- Dynamics and calcium sensitivity of the Ca2+/myristoyl switch protein hippocalcin in living cellsThe Journal of cell biology, 2003
- Seven-transmembrane receptorsNature Reviews Molecular Cell Biology, 2002