β-blockers augment L-type Ca2+ channel activity by targeting spatially restricted β2AR signaling in neurons
Year: 2019
Type: article
Abstract: 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 β 2 AR 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 β 2 AR 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 β 2 AR 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.
Source: eLife
DOI: 10.7554/elife.49464
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Awards: Coupling of vascular CaV1.2 channels in health and disease, Predoctoral Training in Pharmacological Sciences, Calcium Sparklers-Induced Vascular Dysfunction During Diabetes, G346902623, G3750159338, Novel mechanism on subpopulation-dependent biased GPCR signaling in neurons, A single amino acid in CaV1.2 controls channel activity and arterial tone in hypertension, G7737658675, Dysregulation of Cav1.2 by beta amyloid peptide
OpenAlex ID: W2979829572