β-blockers augment L-type Ca2+ channel activity by targeting spatially restricted β2AR signaling in neurons

Ao Shen, Dana Chen, Mampreet Kaur, Peter Bartels, Bing Xu, Qian Shi, Joseph M. Martinez, Kwun Nok Mimi Man, Madeline Nieves-Cintron, Johannes W. Hell, Manuel F. Navedo, Xi Yong Yu, Yang K. Xiang

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish (US)
Article numbere49464
JournaleLife
Volume8
DOIs
StatePublished - Oct 2019

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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