Journal article
beta-blockers augment L-type Ca2+ channel activity by targeting spatially restricted beta(2)AR signaling in neurons
eLife, Vol.8, e49464
10/14/2019
DOI: 10.7554/eLife.49464
PMCID: PMC6813027
PMID: 31609201
Abstract
G protein-coupled receptors (GPCRs) transduce pleiotropic intracellular signals in mammalian cells. Here, we report neuronal excitability of beta-blockers carvedilol and alprenolol at clinically relevant nanomolar concentrations. Carvedilol and alprenolol activate beta(2)AR, 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 beta(2)AR, 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 beta(2)AR that lacks the catecholamine binding pocket. This mutant is preferentially activated by carvedilol but not the orthosteric agonist isoproterenol. Carvedilol activates the mutant beta(2)AR in mouse hippocampal neurons augmenting LTCC activity through cAMP/PKA signaling. Together, our study identifies a mechanism by which beta-blocker-dependent activation of GPCRs promotes spatially restricted cAMP/PKA signaling to selectively target membrane downstream effectors such as LTCC in neurons.
Details
- Title: Subtitle
- beta-blockers augment L-type Ca2+ channel activity by targeting spatially restricted beta(2)AR signaling in neurons
- Creators
- Ao Shen - University of California, DavisDana Chen - University of California, DavisMampreet Kaur - University of California, DavisPeter Bartels - University of California, DavisBing Xu - University of California, DavisQian Shi - University of California, DavisJoseph M. Martinez - University of California, DavisKwun-nok Mimi Man - University of California, DavisMadeline Nieves-Cintron - University of California, DavisJohannes W. Hell - University of California, DavisManuel F. Navedo - University of California, DavisXi-Yong Yu - Guangzhou Medical UniversityYang K. Xiang - University of California, Davis
- Resource Type
- Journal article
- Publication Details
- eLife, Vol.8, e49464
- DOI
- 10.7554/eLife.49464
- PMID
- 31609201
- PMCID
- PMC6813027
- NLM abbreviation
- Elife
- ISSN
- 2050-084X
- eISSN
- 2050-084X
- Publisher
- Elife Sciences Publications Ltd
- Number of pages
- 22
- Grant note
- T32GM099608 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) GM129376; HL098200; HL121059; HL149127 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA American Heart Association R01AG055357 / NATIONAL INSTITUTE ON AGING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) R01HL149127 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) I01BX002900 / Veterans Affairs; US Department of Veterans Affairs BX002900 / U.S. Department of Veterans Affairs; US Department of Veterans Affairs
- Language
- English
- Date published
- 10/14/2019
- Academic Unit
- Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984359567302771
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