Correction: Maning et al. Antagonistic Roles of GRK2 and GRK5 in Cardiac Aldosterone Signaling Reveal GRK5-Mediated Cardioprotection via Mineralocorticoid Receptor Inhibition. Int. J. Mol. Sci. 2020, 21, 2868.

The authors wish to make the following correction to this paper [...].

Signaling and function of cardiac autonomic nervous system receptors: Insights from the GPCR signalling universe.

The two branches of the autonomic nervous system (ANS), adrenergic and cholinergic, exert a multitude of effects on the human myocardium thanks to the activation of distinct G protein-coupled receptors (GPCRs) expressed on the plasma membranes of cardiac myocytes, cardiac fibroblasts, and coronary vascular endothelial cells. Norepinephrine (NE)/epinephrine (Epi) and acetylcholine (ACh) are released from cardiac ANS terminals and mediate the biological actions of the ANS on the heart via stimulation of cardiac adrenergic or muscarinic receptors, respectively. In addition, several other neurotransmitters/hormones act as facilitators of ANS neurotransmission in the heart, taking part in the so-called nonadrenergic noncholinergic (NANC) part of the ANS's control of cardiac function. These NANC mediators also use several different cell membrane-residing GPCRs to exert their effects in the myocardium. Cardiac ANS dysfunction and an imbalance between the activities of its two branches underlie a variety of cardiovascular diseases, from heart failure and hypertension to coronary artery disease, myocardial ischemia, and arrhythmias. In this review, we present the main well-established signaling modalities used by cardiac autonomic GPCRs, including receptors for salient NANC mediators, and we also highlight the latest developments pertaining to cardiac cell type-specific signal transduction, resulting in cell type-specific cardiac effects of each of these autonomic receptors.

Antagonistic Roles of GRK2 and GRK5 in Cardiac Aldosterone Signaling Reveal GRK5-Mediated Cardioprotection via Mineralocorticoid Receptor Inhibition.

Aldosterone (Aldo), when overproduced, is a cardiotoxic hormone underlying heart failure and hypertension. Aldo exerts damaging effects via the mineralocorticoid receptor (MR) but also activates the antiapoptotic G protein-coupled estrogen receptor (GPER) in the heart. G protein-coupled receptor (GPCR)-kinase (GRK)-2 and -5 are the most abundant cardiac GRKs and phosphorylate GPCRs as well as non-GPCR substrates. Herein, we investigated whether they phosphorylate and regulate cardiac MR and GPER. To this end, we used the cardiomyocyte cell line H9c2 and adult rat ventricular myocytes (ARVMs), in which we manipulated GRK5 protein levels via clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and GRK2 activity via pharmacological inhibition. We report that GRK5 phosphorylates and inhibits the cardiac MR whereas GRK2 phosphorylates and desensitizes GPER. In H9c2 cardiomyocytes, GRK5 interacts with and phosphorylates the MR upon ß2-adrenergic receptor (AR) activation. In contrast, GRK2 opposes agonist-activated GPER signaling. Importantly, GRK5-dependent MR phosphorylation of the MR inhibits transcriptional activity, since aldosterone-induced gene transcription is markedly suppressed in GRK5-overexpressing cardiomyocytes. Conversely, GRK5 gene deletion augments cardiac MR transcriptional activity. ß2AR-stimulated GRK5 phosphorylates and inhibits the MR also in ARVMs. Additionally, GRK5 is necessary for the protective effects of the MR antagonist drug eplerenone against Aldo-induced apoptosis and oxidative stress in ARVMs. In conclusion, GRK5 blocks the cardiotoxic MR-dependent effects of Aldo in the heart, whereas GRK2 may hinder beneficial effects of Aldo through GPER. Thus, cardiac GRK5 stimulation (e.g., via ß2AR activation) might be of therapeutic value for heart disease treatment via boosting the efficacy of MR antagonists against Aldo-mediated cardiac injury.