Sustained GRK2-dependent CREB activation is essential for α2-adrenergic receptor-induced PC12 neuronal differentiation

Karkoulias, G.; McCrink, Katie A; Maning, Jennifer; Pollard, Celina M; Desimine, Victoria L; Patsouras, Nicholas; Psallidopoulos, Miltiades C.; Taraviras, Stavros; Lymperopoulos, Anastasios; Flordellis, Christodoulos S.

doi:10.1016/j.cellsig.2019.109446

Cited by 8 publications

(10 citation statements)

References 31 publications

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“…TH catalyzes the rate-limiting step in catecholamine biosynthesis, i.e., the conversion of tyrosine to L-DOPA (L-3′,4′-dihydroxyphenyalalanine) [ 54 ]. The mechanism probably involves activation of the transcription factor CREB (cAMP response element-binding protein) [ 59 , 60 ]. GRK2-mediated TH upregulation results in increased catecholamine (norepinephrine and epinephrine) biosynthesis in the adrenal medulla [ 53 ].…”

Section: Research Hypothesis: Dapagliflozin Attenuates Adrenal Catecholamine Productionmentioning

confidence: 99%

Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research Hypothesis for Dapagliflozin’s Effects in the Adrenal Gland

Lymperopoulos

Borges

Cora

et al. 2021

IJMS

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Heart failure (HF) remains the leading cause of morbidity and death in the western world, and new therapeutic modalities are urgently needed to improve the lifespan and quality of life of HF patients. The sodium-glucose co-transporter-2 (SGLT2) inhibitors, originally developed and mainly indicated for diabetes mellitus treatment, have been increasingly shown to ameliorate heart disease, and specifically HF, in humans, regardless of diabetes co-existence. Indeed, dapagliflozin has been reported to reduce cardiovascular mortality and hospitalizations in patients with HF and reduced ejection fraction (HFrEF). This SGLT2 inhibitor demonstrates these benefits also in non-diabetic subjects, indicating that dapagliflozin’s efficacy in HF is independent of blood glucose control. Evidence for the effectiveness of various SGLT2 inhibitors in providing cardiovascular benefits irrespective of their effects on blood glucose regulation have spurred the use of these agents in HFrEF treatment and resulted in FDA approvals for cardiovascular indications. The obvious question arising from all these studies is, of course, which molecular/pharmacological mechanisms underlie these cardiovascular benefits of the drugs in diabetics and non-diabetics alike. The fact that SGLT2 is not significantly expressed in cardiac myocytes (SGLT1 appears to be the dominant isoform) adds even greater perplexity to this answer. A variety of mechanisms have been proposed over the past few years and tested in cell and animal models and prominent among those is the potential for sympatholysis, i.e., reduction in sympathetic nervous system activity. The latter is known to be high in HF patients, contributing significantly to the morbidity and mortality of the disease. The present minireview first summarizes the current evidence in the literature supporting the notion that SGLT2 inhibitors, such as dapagliflozin and empagliflozin, exert sympatholysis, and also outlines the main putative underlying mechanisms for these sympatholytic effects. Then, we propose a novel hypothesis, centered on the adrenal medulla, for the sympatholytic effects specifically of dapagliflozin. Adrenal medulla is responsible for the production and secretion of almost the entire amount of circulating epinephrine and of a significant percentage of circulating norepinephrine in the human body. If proven true experimentally, this hypothesis, along with other emerging experimental evidence for sympatholytic effects in neurons, will shed new light on the pharmacological effects that mediate the cardiovascular benefits of SGLT2 inhibitor drugs, independently of their blood glucose-lowering effects.

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Section: Research Hypothesis: Dapagliflozin Attenuates Adrenal Catecholamine Productionmentioning

confidence: 99%

Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research Hypothesis for Dapagliflozin’s Effects in the Adrenal Gland

Lymperopoulos

Borges

Cora

et al. 2021

IJMS

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“…Evidence has previously been presented suggesting that hesperetin-mediated TrkA could activate PKA and CREB in PC12 cells. 18 Additionally, Karkoulias et al 44 ubiquitination of TrkA and activate cAMP pathway for protection against H9c2 cell apoptosis and oxidative stress injury (Figure 9).…”

Section: Discussionmentioning

confidence: 99%

“…Evidence has previously been presented suggesting that hesperetin-mediated TrkA could activate PKA and CREB in PC12 cells. 18 Additionally, Karkoulias et al 44…”

Section: Discussionmentioning

confidence: 99%

microRNA‐454‐mediated NEDD4‐2/TrkA/cAMP axis in heart failure: Mechanisms and cardioprotective implications

Wang

Pan

Bai

et al. 2021

J Cellular Molecular Medi

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The current study aimed to investigate the mechanism by which miR‐454 influences the progression of heart failure (HF) in relation to the neural precursor cell expressed, developmentally downregulated 4‐2 (NEDD4‐2)/tropomyosin receptor kinase A (TrkA)/cyclic adenosine 3',5'‐monophosphate (cAMP) axis. Sprague‐Dawley rats were used to establish a HF animal model via ligation of the left anterior descending branch of the coronary artery. The cardiomyocyte H9c2 cells were treated with H2O2 to stimulate oxidative stress injury in vitro. RT‐qPCR and Western blot assay were subsequently performed to determine the expression patterns of miR‐454, NEDD4‐2, TrkA, apoptosis‐related proteins and cAMP pathway markers. Dual‐luciferase reporter gene assay coupled with co‐immunoprecipitation was performed to elucidate the relationship between miR‐454, NEDD4‐2 and TrkA. Gain‐ or loss‐of‐function experiments as well as rescue experiments were conducted via transient transfection (in vitro) and adenovirus infection (in vivo) to examine their respective functions on H9c2 cell apoptosis and myocardial damage. Our results suggested that miR‐454 was aberrantly downregulated in the context of HF, while evidence was obtained suggesting that it targeted NEDD4‐2 to downregulate NEDD4‐2 in cardiomyocytes. miR‐454 exerted anti‐apoptotic and protective effects on cardiomyocytes through inhibition of NEDD4‐2, while NEDD4‐2 stimulated ubiquitination and degradation of TrkA protein. Furthermore, miR‐454 activated the cAMP pathway via the NEDD4‐2/TrkA axis, which ultimately suppressed cardiomyocyte apoptosis and attenuated myocardial damage. Taken together, the key findings of the current study highlight the cardioprotective role of miR‐454, which is achieved through activation of the cAMP pathway by impairing NEDD4‐2‐induced TrkA ubiquitination.

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“…Nevertheless, whether this occurs in cardiac cells or in the myocardium in vivo remains to be seen. Of note, GRK2 was recently shown to mediate sustained activation of α2AR-stimulated CREB in neuronal cells [ 194 ]. Furthermore, α 1 AR signaling may also crosstalk with aldosterone and the MR at the level of PKC activation ( Figure 1 ).…”

Section: Aldosterone-induced Adrenergic Receptor Dysfunction In the Failing Myocardiummentioning

confidence: 99%

Impact of Aldosterone on the Failing Myocardium: Insights from Mitochondria and Adrenergic Receptors Signaling and Function

Guitart‐Mampel

Urquiza

Borges

et al. 2021

Cells

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The mineralocorticoid aldosterone regulates electrolyte and blood volume homeostasis, but it also adversely modulates the structure and function of the chronically failing heart, through its elevated production in chronic human post-myocardial infarction (MI) heart failure (HF). By activating the mineralocorticoid receptor (MR), a ligand-regulated transcription factor, aldosterone promotes inflammation and fibrosis of the heart, while increasing oxidative stress, ultimately induding mitochondrial dysfunction in the failing myocardium. To reduce morbidity and mortality in advanced stage HF, MR antagonist drugs, such as spironolactone and eplerenone, are used. In addition to the MR, aldosterone can bind and stimulate other receptors, such as the plasma membrane-residing G protein-coupled estrogen receptor (GPER), further complicating it signaling properties in the myocardium. Given the salient role that adrenergic receptor (ARs)—particularly βARs—play in cardiac physiology and pathology, unsurprisingly, that part of the impact of aldosterone on the failing heart is mediated by its effects on the signaling and function of these receptors. Aldosterone can significantly precipitate the well-documented derangement of cardiac AR signaling and impairment of AR function, critically underlying chronic human HF. One of the main consequences of HF in mammalian models at the cellular level is the presence of mitochondrial dysfunction. As such, preventing mitochondrial dysfunction could be a valid pharmacological target in this condition. This review summarizes the current experimental evidence for this aldosterone/AR crosstalk in both the healthy and failing heart, and the impact of mitochondrial dysfunction in HF. Recent findings from signaling studies focusing on MR and AR crosstalk via non-conventional signaling of molecules that normally terminate the signaling of ARs in the heart, i.e., the G protein-coupled receptor-kinases (GRKs), are also highlighted.

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Sustained GRK2-dependent CREB activation is essential for α2-adrenergic receptor-induced PC12 neuronal differentiation

Cited by 8 publications

References 31 publications

Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research Hypothesis for Dapagliflozin’s Effects in the Adrenal Gland

Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research Hypothesis for Dapagliflozin’s Effects in the Adrenal Gland

microRNA‐454‐mediated NEDD4‐2/TrkA/cAMP axis in heart failure: Mechanisms and cardioprotective implications

Impact of Aldosterone on the Failing Myocardium: Insights from Mitochondria and Adrenergic Receptors Signaling and Function

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