Discovery of a second citric acid cycle complex.

Together, Nobel Prize honoured work, mathematics, physics and the laws of nature have drawn a concept of clockwise cycling carboxylic acids in Krebs' Citric Acid Cycle. A Citric Acid Cycle complex is defined by specific substrate, product and regulation. Recently, the Citric Acid Cycle 1.

Rethinking the Citric Acid Cycle: Connecting Pyruvate Carboxylase and Citrate Synthase to the Flow of Energy and Material.

In 1937, Sir H. A Krebs first published the Citric Acid Cycle, a unidirectional cycle with carboxylic acids. The original concept of the Citric Acid Cycle from Krebs' 1953 Nobel Prize lecture illustrates the unidirectional degradation of lactic acid to water, carbon dioxide and hydrogen.

The two-cell model of glucose metabolism: a hypothesis of schizophrenia.

Schizophrenia is a chronic and severe mental disorder that affects over 20 million people worldwide. Common symptoms include distortions in thinking, perception, emotions, language, and self awareness. Different hypotheses have been proposed to explain the development of schizophrenia, however, there are no unifying features between the proposed hypotheses.

Astrocytes and neurons communicate via a monocarboxylic acid shuttle.

Since formulation of the Astrocyte-Neuron Lactate Shuttle (ANLS) hypothesis in 1994, the hypothesis has provoked criticism and debate. Our review does not criticise, but rather integrates experimental data characterizing proton-linked monocarboxylate transporters (MCTs) into the ANLS. MCTs have wide substrate specificity and are discussed to be in protein complex with a proton donor (PD).

[Biobanking in Psychiatry].

Medical biobanking is concerned with establishing and maintaining large-scale repositories of biological specimens combined with comprehensive archives of clinical and biographical information on donors. This aims for controlled high and consistent quality of specimens for future biomedical research. One major objective is to assemble multiple blood components for various types of biochemical analysis and experimentation including different isolated cell types.

Proton Transport Chains in Glucose Metabolism: Mind the Proton.

The Embden-Meyerhof-Parnas (EMP) pathway comprises eleven cytosolic enzymes interacting to metabolize glucose to lactic acid [CHCH(OH)COO]. Glycolysis is largely considered as the conversion of glucose to pyruvate (CHCOCOO). We consider glycolysis to be a cellular process and as such, transporters mediating glucose uptake and lactic acid release and enable the flow of metabolites through the cell, must be considered as part of the EMP pathway.

Agonist-dependent and -independent dopamine-1-like receptor signalling differentially regulates downstream effectors.

De-regulation of energy metabolism by the dopaminergic system is linked to neurological diseases such as schizophrenia and bipolar disorder. Inverse agonists are thought to be more beneficial in treating neurological diseases than neutral antagonists, but only limited experimental data are available regarding the impact of constitutive signalling on energy metabolism. The aim of the present study was to assess the impact of constitutive dopamine-1 receptor (D1R) and dopamine-5 receptor (D5R) signalling on downstream targets in transiently and stably transfected HEK293T cells.

Protein phosphatase 2A mediates resensitization of the neurokinin 1 receptor.

Activated G protein-coupled receptors (GPCRs) are phosphorylated and interact with β-arrestins, which mediate desensitization and endocytosis. Endothelin-converting enzyme-1 (ECE-1) degrades neuropeptides in endosomes and can promote recycling. Although endocytosis, dephosphorylation, and recycling are accepted mechanisms of receptor resensitization, a large proportion of desensitized receptors can remain at the cell surface.

Endosomal endothelin-converting enzyme-1: a regulator of beta-arrestin-dependent ERK signaling.

Neuropeptide signaling at the cell surface is regulated by metalloendopeptidases, which degrade peptides in the extracellular fluid, and beta-arrestins, which interact with G protein-coupled receptors (GPCRs) to mediate desensitization. beta-Arrestins also recruit GPCRs and mitogen-activated protein kinases to endosomes to allow internalized receptors to continue signaling, but the mechanisms regulating endosomal signaling are unknown. We report that endothelin-converting enzyme-1 (ECE-1) degrades substance P (SP) in early endosomes of epithelial cells and neurons to destabilize the endosomal mitogen-activated protein kinase signalosome and terminate signaling.

Intracellular degradation of somatostatin-14 following somatostatin-receptor3-mediated endocytosis in rat insulinoma cells.

Somatostatin receptor (SSTR) endocytosis influences cellular responsiveness to agonist stimulation and somatostatin receptor scintigraphy, a common diagnostic imaging technique. Recently, we have shown that SSTR1 is differentially regulated in the endocytic and recycling pathway of pancreatic cells after agonist stimulation. Additionally, SSTR1 accumulates and releases internalized somatostatin-14 (SST-14) as an intact and biologically active ligand.

Endothelin-converting enzyme-1 degrades internalized somatostatin-14.

Agonist-induced internalization of somatostatin receptors (ssts) determines subsequent cellular responsiveness to peptide agonists and influences sst receptor scintigraphy. To investigate sst2A trafficking, rat sst2A tagged with epitope was expressed in human embryonic kidney cells and tracked by antibody labeling. Confocal microscopical analysis revealed that stimulation with sst and octreotide induced internalization of sst2A.

Endothelin-converting enzyme-1 regulates endosomal sorting of calcitonin receptor-like receptor and beta-arrestins.

Although cell surface metalloendopeptidases degrade neuropeptides in the extracellular fluid to terminate signaling, the function of peptidases in endosomes is unclear. We report that isoforms of endothelin-converting enzyme-1 (ECE-1a-d) are present in early endosomes, where they degrade neuropeptides and regulate post-endocytic sorting of receptors. Calcitonin gene-related peptide (CGRP) co-internalizes with calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), beta-arrestin2, and ECE-1 to early endosomes, where ECE-1 degrades CGRP.

Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases.

Proteinase-activated receptor-2 (PAR2) is a seven transmembrane spanning, G-protein-coupled receptor, present on the membrane of many cell types including keratinocytes. In skin, PAR2 is suggested to play a regulatory role during inflammation, epidermal barrier function, and pruritus. PAR2 is activated by trypsin-like proteases by a unique mechanism where cleavage of the receptor leads to the release of a small peptide, which activates the receptor as a tethered ligand.

Endothelin-converting enzyme 1 degrades neuropeptides in endosomes to control receptor recycling.

Neuropeptide signaling requires the presence of G protein-coupled receptors (GPCRs) at the cell surface. Activated GPCRs interact with beta-arrestins, which mediate receptor desensitization, endocytosis, and mitogenic signaling, and the peptide-receptor-arrestin complex is sequestered into endosomes. Although dissociation of beta-arrestins is required for receptor recycling and resensitization, the critical event that initiates this process is unknown.

Post-endocytic sorting of calcitonin receptor-like receptor and receptor activity-modifying protein 1.

Calcitonin receptor-like receptor (CLR) and the receptor activity-modifying protein 1 (RAMP1) comprise a receptor for calcitonin gene-related peptide (CGRP). Although CGRP induces endocytosis of CLR/RAMP1, little is known about post-endocytic sorting of these proteins. We observed that the duration of stimulation with CGRP markedly affected post-endocytic sorting of CLR/RAMP1.

Agonist-induced endocytosis of rat somatostatin receptor 1.

Somatostatin-receptor 1 (sst1) is an autoreceptor in the central nervous system that regulates the release of somatostatin. Sst1 is present intracellularly and at the cell surface. To investigate sst1 trafficking, rat sst1 tagged with epitope was expressed in rat insulinoma cells 1046-38 (RIN-1046-38) and tracked by antibody labeling.

Neuronal control of skin function: the skin as a neuroimmunoendocrine organ.

This review focuses on the role of the peripheral nervous system in cutaneous biology and disease. During the last few years, a modern concept of an interactive network between cutaneous nerves, the neuroendocrine axis, and the immune system has been established. We learned that neurocutaneous interactions influence a variety of physiological and pathophysiological functions, including cell growth, immunity, inflammation, pruritus, and wound healing.

Ubiquitin-dependent down-regulation of the neurokinin-1 receptor.

Transient stimulation with substance P (SP) induces endocytosis and recycling of the neurokinin-1 receptor (NK(1)R). The effects of sustained stimulation by high concentrations of SP on NK(1)R trafficking and Ca(2+) signaling, as may occur during chronic inflammation and pain, are unknown. Chronic exposure to SP (100 nm, 3 h) completely desensitized Ca(2+) signaling by wild-type NK(1)R (NK(1)Rwt).

Localization of calcitonin receptor-like receptor and receptor activity modifying protein 1 in enteric neurons, dorsal root ganglia, and the spinal cord of the rat.

Calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) comprise a receptor for calcitonin gene related peptide (CGRP) and intermedin. Although CGRP is widely expressed in the nervous system, less is known about the localization of CLR and RAMP1. To localize these proteins, we raised antibodies to CLR and RAMP1.

Recycling and resensitization of the neurokinin 1 receptor. Influence of agonist concentration and Rab GTPases.

Substance P (SP) induces endocytosis and recycling of the neurokinin 1 receptor (NK1R) in endothelial cells and spinal neurons at sites of inflammation and pain, and it is thus important to understand the mechanism and function of receptor trafficking. We investigated how the SP concentration affects NK1R trafficking and determined the role of Rab GTPases in trafficking. NK1R trafficking was markedly influenced by the SP concentration.

The third intracellular loop and carboxyl tail of neurokinin 1 and 3 receptors determine interactions with beta-arrestins.

Tachykinins interact with three neurokinin receptors (NKRs) that are often coexpressed by the same cell. Cellular responses to tachykinins depend on the NKR subtype that is activated. We compared the colocalization of NK1R and NK3R with beta-arrestins 1 and 2, which play major roles in receptor desensitization, endocytosis, and signaling.

Rab5a and rab11a mediate agonist-induced trafficking of protease-activated receptor 2.

We evaluated the contribution of rab5a and rab11a to trafficking and signaling of protease-activated receptor 2 (PAR2), a receptor for trypsin and tryptase. Agonists stimulated internalization of PAR2 into early endosomes containing rab5a. Dominant negative rab5aS34N disrupted early endosomes and inhibited agonist-stimulated endocytosis of PAR2.