Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apelin is a recently discovered vasoactive peptide that has been demonstrated to be the endogenous ligand of the APJ receptor. It was named 'apelin' after APJ endogenous ligand. This G protein-coupled receptor (GPCR), originally identified by O'Dowd et al. in 1993, has a close identity with the angiotensin II type 1 (AT1) receptor, but does not bind angiotensin-II. Although apelin and APJ have been found to be ubiquitously expressed in peripheral tissues, particularly the heart and lungs, as well as various regions of the central nervous system, the physiologic actions of apelin remain largely unknown. Nevertheless, some cardiovascular functions of the apelin/APJ system have been described, such as endothelium-dependent vasodilatation, vasoconstriction by direct action on the smooth muscle and positive inotropism. Other reported physiologic actions of apelin include: (1) its role as endocrine adipokine; (2) contribution to fluid homeostasis and thirst regulation; (3) participation as coreceptor in the process of human immunodeficiency virus type 1 infection; and (4) regulation of immune response. The involvement of apelin/APJ in the pathophysiology of heart failure (HF) and its potential as a therapeutic target in this syndrome have also been proposed. In the course of HF progression, plasma levels of apelin are significantly increased in the early stages, decreasing progressively towards normal in the advanced stages of the disease. Given the increasing number of studies focusing on the apelin/APJ system, the goal of this paper was to make an up-to-date review of existing information on apelin and APJ, with particular focus on their cardiovascular actions and potential use as a therapeutic target in HF.
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PMID:Apelin: a novel neurohumoral modulator of the cardiovascular system. Pathophysiologic importance and potential use as a therapeutic target. 1639 42

Several G protein-coupled receptors (GPCRs) mediate neuronal cell migration and survival upon activation by their native peptide ligands but activate death-signaling pathways when activated by certain non-native ligands. In cultured neurons, we recently described expression of the unique seven-transmembrane (7TM) -G protein-coupled receptor, APJ, which is also strongly expressed in neurons in the brain and various cell types in other tissues. We now demonstrate that the endogenous APJ peptide ligand apelin activates signaling pathways in rat hippocampal neurons and modulates neuronal survival. We found that (i) both APJ and apelin are expressed in hippocampal neurons; (ii) apelin peptides induce phosphorylation of the cell survival kinases AKT and Raf/ERK-1/2 in hippocampal neurons; and (iii) apelin peptides protect hippocampal neurons against NMDA receptor-mediated excitotoxicity, including that induced by human immunodeficiency virus type 1. Thus, apelin/APJ signaling likely represents an endogenous hippocampal neuronal survival response, and therefore apelin should be further investigated as a potential neuroprotectant against hippocampal injury.
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PMID:Apelin, an endogenous neuronal peptide, protects hippocampal neurons against excitotoxic injury. 1776 4

Apelin peptides are the cognate ligands for the G-protein coupled receptor APJ, with functions in the cardiovascular and central nervous systems, in glucose metabolism and as a human immunodeficiency virus (HIV-1) coreceptor. Apelin is found in 13-36 residue forms in vivo. The structures of five isoforms of apelin at physiological versus low (5-6 degrees C) temperature are compared here using circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy, demonstrating increased structure at low temperature. Far-ultraviolet (UV) CD spectra are predominantly random coil for apelin isoforms, but are convoluted by unusual bands from the C-terminal phenylalanine side chain. These bands, assigned using F13A-apelin-13, are accentuated at 5 degrees C and imply conformational restriction. At 35 degrees C, the R6-L9 region of apelin-17 is well structured, consistent with previous mutagenesis results showing necessity of this segment for apelin-APJ binding and activation. At 5 degrees C, R6-L9 retains its structuring while the functionally critical C-terminal G13-F17 region also becomes highly structured. Type IV beta-turns and some polyproline-II structure alongside F17 side chain motional reduction correlate well with CD spectral properties. Cis-trans peptide bond isomerization at P14 and P16 produces two sequentially assignable conformers (both trans:both cis approximately 4:1) alongside less populated conformers. Chemical shift assignment of apelin-12, -13 and pyroglutamate-apelin-13 implies highly similar structuring and the same isomerization at the C-terminus. Based on the apelin-17 structure, a two-step binding and activation mechanism is hypothesized.
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PMID:Structural insight into G-protein coupled receptor binding by apelin. 1912 78

G-protein coupled receptors (GPCRs) comprise a large family of membrane proteins with rich functional diversity. Signaling through the apelin receptor (AR or APJ) influences the cardiovascular system, central nervous system and glucose regulation. Pathophysiological involvement of apelin has been shown in atherosclerosis, cancer, human immunodeficiency virus-1 (HIV-1) infection and obesity. Here, we present the high-resolution nuclear magnetic resonance (NMR) spectroscopy-based structure of the N-terminus and first transmembrane (TM) segment of AR (residues 1-55, AR55) in dodecylphosphocholine micelles. AR55 consists of two disrupted helices, spanning residues D14-K25 and A29-R55(1.59). Molecular dynamics (MD) simulations of AR built from a hybrid of experimental NMR and homology model-based restraints allowed validation of the AR55 structure in the context of the full-length receptor in a hydrated bilayer. AR55 structural features were functionally probed using mutagenesis in full-length AR through monitoring of apelin-induced extracellular signal-regulated kinase (ERK) phosphorylation in transiently transfected human embryonic kidney (HEK) 293A cells. Residues E20 and D23 form an extracellular anionic face and interact with lipid headgroups during MD simulations in the absence of ligand, producing an ideal binding site for a cationic apelin ligand proximal to the membrane-water interface, lending credence to membrane-catalyzed apelin-AR binding. In the TM region of AR55, N46(1.50) is central to a disruption in helical character. G42(1.46), G45(1.49) and N46(1.50), which are all involved in the TM helical disruption, are essential for proper trafficking of AR. In summary, we introduce a new correlative NMR spectroscopy and computational biochemistry methodology and demonstrate its utility in providing some of the first high-resolution structural information for a peptide-activated GPCR TM domain.
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PMID:Structural features of the apelin receptor N-terminal tail and first transmembrane segment implicated in ligand binding and receptor trafficking. 2343 63

Very little information is available on the involvement of newly characterized adipokines in human immunodeficiency virus (HIV)/antiretroviral therapy (ART)-associated lipodystrophy syndrome (HALS). Our aim was to determine whether apelin, apelin receptor, omentin, RBP4, vaspin and visfatin genetic variants and plasma levels are associated with HALS. We performed a cross-sectional multicentre study that involved 558 HIV type 1-infected patients treated with a stable highly active ART regimen, 240 of which had overt HALS and 318 who did not have HALS. Epidemiologic and clinical variables were determined. Polymorphisms in the apelin, omentin, RBP4, vaspin and visfatin genes were assessed by genotyping. Plasma apelin, apelin receptor, omentin, RBP4, vaspin and visfatin levels were determined by enzyme-linked immunosorbent assay in 163 patients (81 with HALS and 82 without HALS) from whom stored plasma samples were available. Student's t test, one-way ANOVA, chi-square test, Pearson and Spearman correlations and linear regression analysis were used for statistical analyses. There were no associations between the different polymorphisms assessed and the HALS phenotype. Circulating RBP4 was significantly higher (p < 0.001) and plasma omentin was significantly lower (p 0.001) in patients with HALS compared to those without HALS; differences in plasma levels of the remaining adipokines were nonsignificant between groups. Circulating RBP4 concentration was predicted independently by the presence of HALS. Apelin and apelin receptor levels were independently predicted by body mass index. Visfatin concentration was predicted independently by the presence of acquired immunodeficiency syndrome. HALS is associated with higher RBP4 and lower omentin in plasma. These two adipokines, particularly RBP4, may be a link between HIV/ART and fat redistribution syndromes.
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PMID:HIV/antiretroviral therapy-related lipodystrophy syndrome (HALS) is associated with higher RBP4 and lower omentin in plasma. 2588 66


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