RT Journal Article
SR Electronic
T1 β-blockers augment L-type Ca2+ channel activity by target-selective spatially restricted β2AR-cAMP-PKA signaling in neurons
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 668913
DO 10.1101/668913
A1 Ao Shen
A1 Dana Chen
A1 Manpreet Kaur
A1 Bing Xu
A1 Qian Shi
A1 Joseph M. Martinez
A1 Kwun-nok Mimi Man
A1 Johannes W. Hell
A1 Manuel F. Navedo
A1 Xi-Yong Yu
A1 Yang K. Xiang
YR 2019
UL http://biorxiv.org/content/early/2019/06/13/668913.abstract
AB G protein-coupled receptors (GPCRs) transduce pleiotropic intracellular signals in mammalian cells. Here, we report that some antagonists of β adrenergic receptors (βARs) such as β-blocker carvedilol and alprenolol activate β2AR at nanomolar concentrations, which promote G protein signaling and cAMP/PKA activity without action of G protein receptor kinases (GRKs). The cAMP/PKA signal is restricted within the local plasma membrane domain, leading to selectively enhance PKA-dependent augment of endogenous L-type calcium channel (LTCC) activity but not AMPA receptor in hippocampal neurons. Moreover, we have engineered a mutant β2AR that lacks serine 204 and 207 in the catecholamine binding pocket. This mutant can be preferentially activated by carvedilol but not the orthosteric agonist isoproterenol. Carvedilol activates the mutant β2AR in hippocampal neurons augmenting LTCC activity through cAMP/PKA signaling. Together, our study identifies a mechanism by which β-blocker-dependent activation of GPCRs at low ligand concentrations promotes local cAMP/PKA signaling to selectively target membrane downstream effectors such as LTCC in neurons.