β-blockers augment L-type Ca2+ channel activity by targeting spatially restricted β2AR signaling in neurons
- Guangzhou Medical University, China
- University of California, Davis, United States
Abstract
G protein-coupled receptors (GPCRs) transduce pleiotropic intracellular signals in mammalian cells. Here, we report neuronal excitability of β-blockers carvedilol and alprenolol at clinically relevant nanomolar concentrations. Carvedilol and alprenolol activate β2AR, which promote G protein signaling and cAMP/PKA activities without action of G protein receptor kinases (GRKs). The cAMP/PKA activities are restricted within the immediate vicinity of activated β2AR, leading to selectively enhance PKA-dependent phosphorylation and stimulation of endogenous L-type calcium channel (LTCC) but not AMPA receptor in rat hippocampal neurons. Moreover, we have engineered a mutant β2AR that lacks the catecholamine binding pocket. This mutant is preferentially activated by carvedilol but not the orthosteric agonist isoproterenol. Carvedilol activates the mutant β2AR in mouse hippocampal neurons augmenting LTCC activity through cAMP/PKA signaling. Together, our study identifies a mechanism by which β-blocker-dependent activation of GPCRs promotes spatially restricted cAMP/PKA signaling to selectively target membrane downstream effectors such as LTCC in neurons.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2, 3, 4, and 5.
Article and author information
Author details
Funding
National Institutes of Health (129376)
- Yang K Xiang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Mark T Nelson, University of Vermont, United States
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#20234) of the University of California at Davis. Every effort was made to minimize suffering.
Version history
- Received: June 18, 2019
- Accepted: October 13, 2019
- Accepted Manuscript published: October 14, 2019 (version 1)
- Version of Record published: October 24, 2019 (version 2)
- Version of Record updated: December 2, 2019 (version 3)
Copyright
© 2019, Shen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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β-blockers augment L-type Ca2+ channel activity by targeting spatially restricted β2AR signaling in neurons
eLife 8:e49464.
https://doi.org/10.7554/eLife.49464
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