Succinate modulates Ca2+ transient and cardiomyocyte viability through PKA-dependent pathway

Aguiar, Carla; Andrade, Vanessa L.; Gomes, Enéas Ricardo de Morais; Alves, Marcia N.; Ladeira, Marina; Pinheiro, Ana Cristina N.; Gomes, Dawidson Assis; Almeida, Alvair P.; Góes, Alfredo M.; Resende, Rodrigo R.; Guatimosim, Sílvia; Leite, M. Fátima

doi:10.1016/j.ceca.2009.11.003

Cited by 65 publications

(73 citation statements)

References 38 publications

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“…Succinate and succinate receptor 1 (SUCNR1) signaling during inflammation Another function for succinate in inflammation is as the ligand for the G protein-coupled receptor (GPCR) GPR91, [45]. SUCNR1 engagement activates phospholipase C (PLC), resulting in cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol trisphosphate (IP3) and diacylglycerol (DAG).…”

Section: Succinate and Hif-1a In Inflammationmentioning

confidence: 99%

Succinate: a metabolic signal in inflammation

Mills

O’Neill

2014

Trends in Cell Biology

517

445

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Succinate is an intermediate of the tricarboxylic acid (TCA) cycle, and plays a crucial role in adenosine triphosphate (ATP) generation in mitochondria. Recently, new roles for succinate outside metabolism have emerged. Succinate stabilizes the transcription factor hypoxia-inducible factor-1a (HIF-1a) in specific tumors and in activated macrophages, and stimulates dendritic cells via its receptor succinate receptor 1. Furthermore, succinate has been shown to post-translationally modify proteins. This expanding repertoire of functions for succinate suggests a broader role in cellular activation. We review the new roles of succinate and draw parallels to other metabolites such as NAD + and citrate whose roles have expanded beyond metabolism and into signaling. Metabolic alterations influence the immune responseThe immune system acts as an internal shield defending against invading pathogens and is made up of an innate system, including macrophages, neutrophils, and dendritic cells (DCs), and an adaptive system composed of T and B lymphocytes. Cells of the innate immune system recognize pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), present on their cell surface and in the cytosol [1]. Once activated, innate immune cells can initiate adaptive immunity to fight infection further and to generate immunological memory. In resting conditions these cells are relatively inactive; however, upon recognition of foreign material they have the ability to respond rapidly, producing a wide array of mediators such as cytokines, chemokines, and antimicrobial peptides to clear the infection.Such rapid induction of immunity represents a significant metabolic demand. In recent years it has become evident that immune cells have the ability to shift their metabolism under varying conditions and that this is essential for proper immune function [2]. Stimulation of DCs and macrophages can result in a decrease in oxidative phosphorylation, which is normally employed under resting conditions, with a concomitant increase in glycolysis and the pentose-phosphate pathway [3,4]. This switch to glycolysis rapidly generates ATP to maintain mitochondrial membrane potential and energy homeostasis, ultimately ensuring cell viability [5]. It also provides biosynthetic precursors required for proliferating cells and for cells with a prodigious biosynthetic capacity, such as macrophages when they are activated to produce cytokines. This altered metabolism is similar to the Warburg effect (aerobic glycolysis) observed in tumor cells [6] (Figure 1, Box 1). Indeed, the metabolic sensor HIF-1a can determine the growth and fate of both tumor cells and immune cells. For example, HIF-1a activation favors differentiation of T lymphocytes into proinflammatory Th17 cells and attenuates regulatory T cell development [7]. Importantly, as well as global changes in metabolism that occur in activated immune cells, individual metabolites, including succinate, citrate, and NAD + , have been d...

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Section: Succinate and Hif-1a In Inflammationmentioning

confidence: 99%

Succinate: a metabolic signal in inflammation

Mills

O’Neill

2014

Trends in Cell Biology

517

445

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“…In these cells, SUCNR1 activation triggers hypertrophic gene expression via ERK1/2 phosphorylation, increased expression of calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ) and the translocation of histone deacetylase 5 (HDAC5) into the cytoplasm (Aguiar et al, 2014). Moreover, it was shown in another study by the same group as for cardiomyocytes, SUCNR1 alters Ca 2+ transient via AC and protein kinase A (PKA) activation that phosphorylate phospholamban (PLN) and ryanodine receptor 2 (RyR2), two well-known Ca 2+ handling proteins (Aguiar et al, 2010). These results suggest a G s -mediated effect.…”

Section: Hypertensionmentioning

confidence: 98%

“…Succinate binding to SUCNR1 triggers the activation of mitogen-activated pathway (MAP) kinases, especially extracellular signal-regulated kinases 1 and 2 (ERK1/2) in HEK293 cell line (Gilissen etal., 2015;He et al, 2004), MDCK (Robben et al, 2009), immature dendritic cells (iDC) (Rubic et al, 2008), retinal ganglion neuronal cell line (RGC) (Hu et al, 2013), TF-1 (human erythroleukaemia cell line) and cardiomyocytes (Aguiar et al, 2010) (Fig. 3).…”

Section: Succinate Receptor 1 Signaling Pathwaysmentioning

confidence: 99%

“…Hence, as an indirect example of chronic hypertension, serum succinate levels are increased in patients suffering from cardiac hypertrophy (CH) (Aguiar et al, 2014). Activated SUCNR1 may indirectly contribute to CH by inducing hypertension but might also have a direct action because it is expressed at protein level in ventricular cardiomyocytes (in sarcolemmal membrane and T-tubules) (Aguiar et al, 2010;Aguiar et al, 2014). In these cells, SUCNR1 activation triggers hypertrophic gene expression via ERK1/2 phosphorylation, increased expression of calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ) and the translocation of histone deacetylase 5 (HDAC5) into the cytoplasm (Aguiar et al, 2014).…”

Section: Hypertensionmentioning

confidence: 99%

“…These results suggest a G s -mediated effect. However, the data are difficult to interpret because the concentration of succinate used was very high (10 mM) and the direct interaction of the receptor with G s was not demonstrated (Aguiar et al, 2010).…”

Section: Hypertensionmentioning

confidence: 99%

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Insight into SUCNR1 (GPR91) structure and function

Gilissen

Jouret

Pirotte

et al. 2016

Pharmacology & Therapeutics

103

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SUCNR1 (or GPR91) belongs to the family of G protein-coupled receptors (GPCR), which represents the largest group of membrane proteins in human genome. The majority of marketed drugs targets GPCRs, directly or indirectly. SUCNR1 has been classified as an orphan receptor until a landmark study paired it with succinate, a citric acid cycle intermediate.According to the current paradigm, succinate triggers SUCNR1 signaling pathways to indicate local stress that may affect cellular metabolism. SUCNR1 implication has been well documented in renin-induced hypertension, ischemia/reperfusion injury, inflammation and immune response, platelet aggregation and retinal angiogenesis. In addition, the SUCNR1-induced increase of blood pressure may contribute to diabetic nephropathy or cardiac hypertrophy.The understanding of SUCNR1 activation, signaling pathways and functions remains largely elusive, which calls for deeper investigations. SUCNR1 shows a high potential as an innovative drug target and is probably an important regulator of basic physiology. In order to achieve the full characterization of this receptor, more specific pharmacological tools such as small-molecules modulators will represent an important asset. In this review, we describe the structural features of SUCNR1, its current ligands and putative binding pocket. We give an exhaustive overview of the known and hypothetical signaling partners of the receptor in different in vitro and in vivo systems. The link between SUCNR1 intracellular pathways and its pathophysiological roles are also extensively discussed.

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Krebs cycle rewired for macrophage and dendritic cell effector functions

2017

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Edited by Laszlo NagyThe Krebs cycle is an amphibolic pathway operating in the mitochondrial matrix of all eukaryotic organisms. In response to proinflammatory stimuli, macrophages and dendritic cells undergo profound metabolic remodelling to support the biosynthetic and bioenergetic requirements of the cell. Recently, it has been discovered that this metabolic shift also involves the rewiring of the Krebs cycle to regulate cellular metabolic flux and the accumulation of Krebs cycle intermediates, notably, citrate, succinate and fumarate. Interestingly, a new role for Krebs cycle intermediates as signalling molecules and immunomodulators that dictate the inflammatory response has begun to emerge. This review will discuss the latest developments in Krebs cycle rewiring and immune cell effector functions, with a particular focus on the regulation of cytokine production.

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Succinate modulates Ca2+ transient and cardiomyocyte viability through PKA-dependent pathway

Cited by 65 publications

References 38 publications

Succinate: a metabolic signal in inflammation

Succinate: a metabolic signal in inflammation

Insight into SUCNR1 (GPR91) structure and function

Krebs cycle rewired for macrophage and dendritic cell effector functions

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