Key Laboratory of Molecular Target and Clinical Pharmacology, State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China; Department of Pharmacology, University of California Davis, Davis, United States
Dana Chen
Department of Pharmacology, University of California Davis, Davis, United States
Manpreet Kaur
Department of Pharmacology, University of California Davis, Davis, United States
Peter Bartels
Department of Pharmacology, University of California Davis, Davis, United States
Bing Xu
Department of Pharmacology, University of California Davis, Davis, United States; VA Northern California Health Care System, Mather, United States
Qian Shi
Department of Pharmacology, University of California Davis, Davis, United States
Joseph M Martinez
Department of Pharmacology, University of California Davis, Davis, United States
Kwun-nok Mimi Man
Department of Pharmacology, University of California Davis, Davis, United States
Madeline Nieves-Cintron
Department of Pharmacology, University of California Davis, Davis, United States
Department of Pharmacology, University of California Davis, Davis, United States
Xi-Yong Yu
Key Laboratory of Molecular Target and Clinical Pharmacology, State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
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.
