Adenosine receptor A2AR is known to antagonize dopaminergic signaling in the striatum and its malfunctions have been implicated in various striatum-related diseases. Flajolet et al. show that A2AR and fibroblast growth factor receptor interact to synergistically activate ERK1/2 pathway and that such interaction modulates the morphological changes of cultured neurons and synaptic plasticity of cortico-striatal synapses. Abnormalities of striatal function have been implicated in several major neurological and psychiatric disorders, including Parkinson's disease, schizophrenia and depression. Adenosine, via activation of A2A receptors, antagonizes dopamine signaling at D2 receptors and A2A receptor antagonists have been tested as therapeutic agents for Parkinson's disease. We found a direct physical interaction between the G protein–coupled A2A receptor (A2AR) and the receptor tyrosine kinase fibroblast growth factor receptor (FGFR). Concomitant activation of these two classes of receptors, but not individual activation of either one alone, caused a robust activation of the MAPK/ERK pathway, differentiation and neurite extension of PC12 cells, spine morphogenesis in primary neuronal cultures, and cortico-striatal plasticity that was induced by a previously unknown A2AR/FGFR-dependent mechanism. The discovery of a direct physical interaction between the A2A and FGF receptors and the robust physiological consequences of this association shed light on the mechanism underlying FGF functions as a co-transmitter and open new avenues for therapeutic interventions.

The epidemic increase of non-alcoholic fatty liver diseases (NAFLD) requires a deeper understanding of the regulatory circuits controlling the response of liver metabolism to nutritional challenges, medical drugs, and genetic enzyme variants. As in vivo studies of human liver metabolism are encumbered with serious ethical and technical issues, we developed a comprehensive biochemistry-based kinetic model of the central liver metabolism including the regulation of enzyme activities by their reactants, allosteric effectors, and hormone-dependent phosphorylation. The utility of the model for basic research and applications in medicine and pharmacology is illustrated by simulating diurnal variations of the metabolic state of the liver at various perturbations caused by nutritional challenges (alcohol), drugs (valproate), and inherited enzyme disorders (galactosemia). Using proteomics data to scale maximal enzyme activities, the model is used to highlight differences in the metabolic functions of normal hepatocytes and malignant liver cells (adenoma and hepatocellular carcinoma).

Because erythropoietin (Epo) is intensively studied as neuroprotective agent, Epo receptor (EpoR) regulation in neurons is of particular interest. Herein, we investigated molecular mechanisms of EpoR regulation in neuronal cells including the role of GATA transcription factors. First, developmental downregulation of EpoR expression in murine brain was observed. A differential expression pattern of the Gata factors was found in these specimens as well as in murine adult neural stem cells (NSC) and primary rat neurons, astrocytes, and microglia. Human SH-SY5Y cells served as a model to analyze EpoR regulation. In vitro binding of GATA-2, -3, and -4 to the 5′-flanking region was demonstrated. In reporter gene assays, the activity of a region containing two GATA binding sites was significantly induced when these GATA factors were overexpressed. However, GATA factors alone did not affect endogenous EpoR expression. Importantly, EpoR transcripts have doubled under hypoxia. Furthermore, we analyzed the methylation pattern close to the GATA motifs. Indeed, demethylation with 5-Aza-2′-deoxycytidine (Aza) resulted in upregulation of EpoR mRNA. Additionally, several CpGs were mostly nonmethylated in SH-SY5Y cells, but methylated in specific regions of the human adult brain. Thus, methylation may be involved in developmental EpoR downregulation.

Background: Many heart diseases can result in reduced pumping capacity of the heart muscle. A mismatch between ATP demand and ATP production of cardiomyocytes is one of the possible causes. Assessment of the relation between myocardial ATP production (MV _ATP ) and cardiac workload is important for better understanding disease development and choice of nutritional or pharmacologic treatment strategies. Because there is no method for measuring MV _ATP in vivo, the use of physiology-based metabolic models in conjunction with protein abundance data is an attractive approach. METHOD: We developed a comprehensive kinetic model of cardiac energy metabolism (CARDIOKIN1) that recapitulates numerous experimental findings on cardiac metabolism obtained with isolated cardiomyocytes, perfused animal hearts, and in vivo studies with humans. We used the model to assess the energy status of the left ventricle of healthy participants and patients with aortic stenosis and mitral valve insufficiency. Maximal enzyme activities were individually scaled by means of protein abundances in left ventricle tissue samples. The energy status of the left ventricle was quantified by the ATP consumption at rest (MV _ATP [rest]), at maximal workload (MV _ATP [max]), and by the myocardial ATP production reserve, representing the span between MV _ATP (rest) and MV _ATP (max). Results: Compared with controls, in both groups of patients, MV _ATP (rest) was increased and MV _ATP (max) was decreased, resulting in a decreased myocardial ATP production reserve, although all patients had preserved ejection fraction. The variance of the energetic status was high, ranging from decreased to normal values. In both patient groups, the energetic status was tightly associated with mechanic energy demand. A decrease of MV _ATP (max) was associated with a decrease of the cardiac output, indicating that cardiac functionality and energetic performance of the ventricle are closely coupled. Conclusions: Our analysis suggests that the ATP-producing capacity of the left ventricle of patients with valvular dysfunction is generally diminished and correlates positively with mechanical energy demand and cardiac output. However, large differences exist in the energetic state of the myocardium even in patients with similar clinical or image-based markers of hypertrophy and pump function. Registration: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT03172338 and NCT04068740.

Cortical spreading depolarization (SD) imposes a massive increase in energy demand and therefore evolves as a target for treatment following acute brain injuries. Anesthetics are empirically used to reduce energy metabolism in critical brain conditions, yet their effect on metabolism during SD remains largely unknown. We investigated oxidative metabolism during SD in brain slices from Wistar rats. Extracellular potassium ([K ⁺ ] _o ), local field potential and partial tissue oxygen pressure (p _ti O ₂ ) were measured simultaneously. The cerebral metabolic rate of oxygen (CMRO ₂ ) was calculated using a reaction-diffusion model. By that, we tested the effect of clinically relevant concentrations of isoflurane on CMRO ₂ during SD and modeled tissue oxygenation for different capillary pO ₂ values. During SD, CMRO ₂ increased 2.7-fold, resulting in transient hypoxia in the slice core. Isoflurane decreased CMRO ₂ , reduced peak [K ⁺ ] _o , and prolonged [K ⁺ ] _o clearance, which indicates reduced synaptic transmission and sodium-potassium ATPase inhibition. Modeling tissue oxygenation during SD illustrates the need for increased capillary pO ₂ levels to prevent hypoxia. In the absence thereof, isoflurane could improve tissue oxygenation by lowering CMRO ₂ . Therefore, isoflurane is a promising candidate for pre-clinical studies on neuronal survival in conditions involving SD.

Myelination enhances the conduction velocity of action potentials (AP) and increases energy efficiency. Thick myelin sheaths are typically found on large-distance axonal connections or in fast-spiking interneurons, which are critical for synchronizing neuronal networks during gamma-band oscillations. Loss of myelin sheath is associated with multiple alterations in axonal architecture leading to impaired AP propagation. While numerous studies are devoted to the effects of demyelination on conduction velocity, the metabolic effects and the consequences for network synchronization have not been investigated. Here we present a unifying computational model for electrophysiology and metabolism of the myelinated axon. The computational model suggested that demyelination not only decreases the AP speed but AP propagation in demyelinated axons requires compensatory processes like mitochondrial mass increase and a switch from saltatory to continuous propagation to rescue axon functionality at the cost of reduced AP propagation speed and increased energy expenditure. Indeed, these predictions were proven to be true in a culture model of demyelination where the pharmacologically-induced loss of myelin was associated with increased oxygen consumption rates, and a significant broadening of bandwidth as well as a decrease in the power of gamma oscillations.