Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The A1-adenosine receptor (A1-AR) is a member of the G-protein coupled receptor superfamily, which has significant pathophysiological importance in disorders such as heart arrhythmias, asthma and stroke. Here, we have used fluorescence correlation spectroscopy (FCS) to facilitate the study of A1-AR pharmacology at the subcellular level. To this end, we have successfully designed and synthesised a fluorescently labelled A1-AR agonist, ABA-BY630. ABA-BY630 is an N6- derivative of adenosine conjugated to the red-excited fluorophore, BODIPY" 630/650. In CHO cells expressing the human A1-AR, ABA-BY630 shows strong and potent agonist activity at this receptor. Specific binding of ABA-BY630 to the A1-AR in cell membranes of living CHO cells can also be visualised using confocal microscopy. Moreover, using FCS, we can detect and quantify the binding of ABA-BY630 to the A1-AR in a small area (0.2 microm2) of the upper cell membrane. FCS measurements indicate the presence of at least two populations of receptor-ABA-BY630 complexes with diffusion times of 8 and 233 ms. The quantity of both of these complexes was significantly reduced by pre-incubation with the A1-AR antagonist DPCPX. Application of FCS in conjunction with ABA-BY630 will allow the comparison of A1-AR pharmacology in single cells from healthy and diseased tissue.
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PMID:Application of fluorescence correlation spectroscopy to the measurement of agonist binding to a G-protein coupled receptor at the single cell level. 1499 7

Protease-activated receptor-1 (PAR1) is a G-protein coupled receptor that is proteolytically activated by blood-derived serine proteases. Although PAR1 is best known for its role in coagulation and hemostasis, recent findings demonstrate that PAR1 activation has actions in the central nervous system (CNS) apart from its role in the vasculature. Rodent studies have demonstrated that PAR1 is expressed throughout the brain on neurons and astrocytes. PAR1 activation in vitro and in vivo appears to influence neurodegeneration and neuroprotection in animal models of stroke and brain injury. Because of increasing evidence that PAR1 has important and diverse roles in the CNS, we explored the protein localization and function of PAR1 in human brain. PAR1 is most intensely expressed in astrocytes of white and gray matter and moderately expressed in neurons. PAR1 and GFAP co-localization demonstrates that PAR1 is expressed on the cell body and on astrocytic endfeet that invest capillaries. PAR1 activation in the U178MG human glioblastoma cell line increased PI hydrolysis and intracellular Ca(2+), indicating that PAR1 is functional in human glial-derived tumor cells. Primary cultures of human astrocytes and human glioblastoma cells respond to PAR1 activation by increasing intracellular Ca(2+). Together, these results demonstrate that PAR1 is expressed in human brain and functional in glial tumors and cultures derived from it. Because serine proteases may enter brain tissue and activate PAR1 when the blood brain barrier (BBB) breaks down, pharmacological manipulation of PAR1 signaling may provide a potential therapeutic target for neuroprotection in human neurological disorders.
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PMID:Protease-activated receptor-1 in human brain: localization and functional expression in astrocytes. 1519 6

In order to identify biological processes relevant for cell death and survival in the brain following stroke, the postischemic brain transcriptome was studied by a large-scale cDNA array analysis of three peri-infarct brain regions at eight time points during the first 24 h of reperfusion following middle cerebral artery occlusion in the rat. K-means cluster analysis revealed two distinct biphasic gene expression patterns that contained 44 genes (including 18 immediate early genes), involved in cell signaling and plasticity (i.e. MAP2K7, Sprouty2, Irs-2, Homer1, GPRC5B, Grasp). The first gene induction phase occurred at 0-3 h of reperfusion, and the second at 9-15 h, and was validated by in situ hybridization. Four gene clusters displayed a progressive increase in expression over time and included 50 genes linked to cell motility, lipid synthesis and trafficking (i.e. ApoD, NPC1, G3P-dehydrogenase1, and Choline kinase) or cell death-regulating genes such as mitochondrial CLIC. We conclude that a biphasic transcriptional up-regulation of the brain-derived neurotrophic factor (BDNF)-G-protein coupled receptor (GPCR)-mitogen-activated protein (MAP) kinase signaling pathways occurs in surviving tissue, concomitant with a progressive and persistent activation of cell proliferation signifying tissue regeneration, which provide the means for cell survival and postischemic brain plasticity.
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PMID:Comprehensive regional and temporal gene expression profiling of the rat brain during the first 24 h after experimental stroke identifies dynamic ischemia-induced gene expression patterns, and reveals a biphasic activation of genes in surviving tissue. 1630 Jun 43

Thromboxane A(2) (TXA(2)) is an arachidonic acid metabolite involved in pathologies such as stroke, myocardial infarction, and atherosclerosis. Consequently, the design of TXA(2) receptor (TP) antagonists remains of great interest in cardiovascular medicine. The actions of TXA(2) are mediated by its specific G-protein coupled receptor of which two alternative spliced isoforms, TPalpha and TPbeta, have been described in humans. In this study, we report the synthesis of a series of original N-alkyl-N'-[2-(cycloalkyl, alkylaryl)-5-nitrobenzenesulfonyl]urea and N-alkyl-N'-[2-(alkylaryl)-5-nitrobenzenesulfonyl]-N' '-cyanoguanidines and outline their pharmacological evaluation using the individual TPalpha and TPbeta isoforms. Among compounds analyzed, several of them exhibited greater affinity and/or functional activity for either TPalpha or TPbeta. The most promising molecules were also found to be antiplatelet agents. From the present results, structural features involved in isoform selectivity can be proposed, and thereby several lead compounds have been identified for the further development of selective TP isoform antagonists.
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PMID:Synthesis and pharmacological evaluation of novel nitrobenzenic thromboxane modulators as antiplatelet agents acting on both the alpha and beta isoforms of the human thromboxane receptor. 1675 13

Prostacyclin (PGI2) is released by vascular endothelial cells and serves as a potent vasodilator, inhibitor of platelet aggregation (anti-thrombotic), and moderator of vascular smooth muscle cell proliferation-migration-differentiation (anti-atherosclerotic). These actions are mediated via a seven transmembrane-spanning G-protein coupled receptor (GPCR), known as the human prostacyclin receptor or hIP. Animal studies using prostacyclin receptor knock-out (IP-/-) mice have revealed increased propensities towards thrombosis, intimal hyperplasia, atherosclerosis, restenosis, as well as reperfusion injury. Of further importance has been the world-wide withdrawal of selective COX-2 inhibitors, due to their discriminating suppression of COX-2-derived PGI2 and its cardioprotective effects, leading to increased cardiovascular events, including myocardial infarction and thrombotic stroke. Over the last decade, mutagenesis studies of the IP receptor, in conjunction with in vitro functional assays and molecular modeling, have provided critical insights into the molecular mechanisms of both agonist binding and receptor activation. Most recently, the discovery of naturally-occurring and dysfunctional mutations within the hIP has provided additional insights into the proposed cardioprotective role of prostacyclin. The aim of this review is to summarize the most recent findings regarding hIP receptor structure-function that have developed through the study of both synthetic and naturally-occurring mutations.
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PMID:Human prostacyclin receptor structure and function from naturally-occurring and synthetic mutations. 1716 37

Alzheimer disease (AD) and stroke are two leading causes of age-associated dementia. Increasing evidence points to vascular damage as an early contributor to the development of AD and AD-like pathology. In this review, we discuss the role of G protein-coupled receptor kinase 2 (GRK2) as it relates to individuals affected by AD and how the cardiovasculature plays a role in AD pathogenesis. The possible involvement of GRKs in AD pathogenesis is an interesting notion, which may help bridge the gap in our understanding of the heartbrain connection in relation to neurovisceral damage and vascular complications in AD, since kinases of this family are known to regulate numerous receptor functions both in the brain, myocardium, and elsewhere. The aim of this review is to discuss our findings of overexpression of GRK2 in the context of the early pathogenesis of AD, because increased levels of GRK2 immunoreactivity were found in vulnerable neurons of AD patients as well as in a two-vessel occlusion (2-VO) mammalian model of ischaemia. Also, we consider the consequences for this overexpression as a loss of G-protein coupled receptor (GPCR) regulation, as well as suggest a potential role for GPCRs and GRKs in a unifying theory of AD pathogenesis, particularly in the context of cerebrovascular disease. We synthesize this newer information and attempt to put it into context with GRKs as regulators of diverse physiological cellular functions that could be appropriate targets for future pharmacological intervention.
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PMID:Insights into cerebrovascular complications and Alzheimer disease through the selective loss of GRK2 regulation. 1929 35

Dyslipidemia is a metabolic disorder that constitutes a major risk factor for cardiovascular diseases and stroke and is often associated with diabetes mellitus and atherosclerosis. In recent years a number of ligand-activated receptors have been found to exert a role in integrating essential steps of lipid and glucose metabolism. Bile acid-activated receptors are a defined subset of nuclear and G-protein coupled receptors mainly expressed in entero-hepatic tissues for which bile acids function as signaling molecules. Primary bile acids (chenodeoxycholic acid and cholic acid) are physiological ligands/activators of farnesoid-X-receptor (FXR), pregnane-X-receptor (PXR) and constitutive androstane receptor (CAR), while litocholic acid is a ligand for the Vitamin D receptor (VDR) and the G-protein coupled receptor TGR5. Despite FXR demonstrates a high selectivity for bile acids, PXR and CAR are relatively promiscuous receptors integrating lipid homeostasis with xenobiotic metabolism. FXR, PXR, CAR and TGR exert synergistic activities in regulating lipid and glucose homeostasis and energy expenditure and liver and peripheral insulin sensitivity. Ligands for these receptors hold promise in the treatment of dyslipidemic conditions as revealed by results of a number of preclinical models but carry a defined risk for potential side effects.
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PMID:Bile acid-activated receptors in the treatment of dyslipidemia and related disorders. 1993 33

Hypertension represents a complex, multifactorial disease and contributes to the major causes of morbidity and mortality in industrialized countries: ischemic and hypertensive heart disease, stroke, peripheral atherosclerosis and renal failure. Current pharmacological therapy of essential hypertension focuses on the regulation of vascular resistance by inhibition of hormones such as catecholamines and angiotensin II, blocking them from receptor activation. Interaction of G-protein coupled receptor kinases (GRKs) and regulator of G-protein signaling (RGS) proteins with activated G-protein coupled receptors (GPCRs) effect the phosphorylation state of the receptor leading to desensitization and can profoundly impair signaling. Defects in GPCR regulation via these modulators have severe consequences affecting GPCR-stimulated biological responses in pathological situations such as hypertension, since they fine-tune and balance the major transmitters of vessel constriction versus dilatation, thus representing valuable new targets for anti-hypertensive therapeutic strategies. Elevated levels of GRKs are associated with human hypertensive disease and are relevant modulators of blood pressure in animal models of hypertension. This implies therapeutic perspective in a disease that has a prevalence of 65million in the United States while being directly correlated with occurrence of major adverse cardiac and vascular events. Therefore, therapeutic approaches using the inhibition of GRKs to regulate GPCRs are intriguing novel targets for treatment of hypertension and heart failure.
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PMID:Regulation of GPCR signaling in hypertension. 2006 Aug 96

Increasing evidence points to vascular damage as an early contributor to the development of two leading causes of age-associated dementia, namely Alzheimer disease (AD) and AD-like pathology such as stroke. This review focuses on the role of G protein-coupled receptor kinases (GRKs) as they relate to dementia and how the cardio and cerebrovasculature is involved in AD pathogenesis. The exploration of GRKs in AD pathogenesis may help bridge gaps in our understanding of the heart-brain connection in relation to neurovisceral damage and vascular complications of AD. The a priori basis for this inquiry stems from the fact that kinases of this family regulate numerous receptor functions in the brain, myocardium and elsewhere. The aim of this review is to discuss the finding of GRK2 overexpression in the context of early AD pathogenesis. Also, we consider the consequences for this overexpression as a loss of G-protein coupled receptor (GPCR) regulation, as well as suggest a potential role for GPCRs and GRKs in a unifying theory of AD pathogenesis through the cerebrovasculature. Finally, we synthesize this newer information in an attempt to put it into context with GRKs as regulators of cellular function, which makes these proteins potential diagnostic and therapeutic targets for future pharmacological intervention.
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PMID:The GRK2 Overexpression Is a Primary Hallmark of Mitochondrial Lesions during Early Alzheimer Disease. 2020 79

Chemokine CXC ligand 12 (CXCL12), originally named stromal cell-derived factor-1 (SDF-1), is a member of the CXC chemokine subfamily. CXCL12 is found to be expressed by all cell types that are presented in the central nervous system (CNS). It works in conjunction with the G-protein coupled receptor CXCR4, which is found at the surface of a variety of cells including neurons, astrocytes, microglia, bone marrow-derived cells, as well as other progenitor cells. Recent studies revealed that CXCL12 could also bind and signal through receptor CXCR7. CXCL12 and CXCR4 are constitutively expressed in the brain but are up-regulated in the ischemic penumbra regions following ischemic stroke. CXCL12/CXCR4 play important roles in multiple processes after ischemic stroke, which include inflammatory response, focal angiogenesis, and the recruitment of bone marrow-derived cells (BMCs) and neural progenitor cell (NPC) to injury. In addition to its roles in stroke pathology, CXCL12 is also thought to be a key regulator in stroke repairing. This review will focus on the function of CXCL12/CXCR4 in post-stroke inflammation and neurovascular repairing. The potential application of CXCL12 modulation in clinical stroke treatment is also discussed.
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PMID:Roles of chemokine CXCL12 and its receptors in ischemic stroke. 2220 16


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