Abstract:
BACKGROUND AND PURPOSE:Chemokines and their receptors form an intricate interaction and signalling network that plays critical roles in various physiological and pathological cellular processes. The high promiscuity and apparent redundancy of this network makes probing individual chemokine/receptor interactions and functional effects, as well as targeting individual receptor axes for therapeutic applications, challenging. Despite poor sequence identity, the N-terminal regions of chemokines, which play a key role in their activity and selectivity, contain several conserved features. Thus far little is known regarding the molecular basis of their interactions with typical and atypical chemokine receptors or the conservation of their contributions across chemokine-receptor pairs. EXPERIMENTAL APPROACH:We used a broad panel of chemokine variants and modified peptides derived from the N-terminal region of chemokines CXCL12, CXCL11 and vCCL2, to compare the contributions of various features to binding and activation of their shared receptors, the two typical, canonical G protein-signalling receptors, CXCR4 and CXCR3, as well as the atypical scavenger receptor CXCR7/ACKR3, which shows exclusively arrestin-dependent activity. KEY RESULTS:We provide molecular insights into the plasticity of the ligand-binding pockets of these receptors, their chemokine binding modes and their activation mechanisms. Although the chemokine N-terminal region is a critical determinant, neither the most proximal residues nor the N-loop are essential for binding and activation of ACKR3, as distinct from binding and activation of CXCR4 and CXCR3. CONCLUSION AND IMPLICATIONS:These results suggest a different interaction mechanism between this atypical receptor and its ligands and illustrate its strong propensity to activation.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Szpakowska M,Nevins AM,Meyrath M,Rhainds D,D'huys T,Guité-Vinet F,Dupuis N,Gauthier PA,Counson M,Kleist A,St-Onge G,Hanson J,Schols D,Volkman BF,Heveker N,Chevigné Adoi
10.1111/bph.14132subject
Has Abstractpub_date
2018-05-01 00:00:00pages
1419-1438issue
9eissn
0007-1188issn
1476-5381journal_volume
175pub_type
杂志文章abstract:BACKGROUND AND PURPOSE:Endogenous cannabinoids (endocannabinoids) in the periaqueductal grey (PAG) play a vital role in mediating stress-induced analgesia. This analgesic effect of endocannabinoids is enhanced by pharmacological inhibition of their degradative enzymes. However, the specific effects of endocannabinoids ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.12839
更新日期:2014-12-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Two of the most relevant unmet needs in epilepsy are represented by the development of disease-modifying drugs able to affect epileptogenesis and/or the study of related neuropsychiatric comorbidities. No systematic study has investigated the effects of chronic treatment with antipsychotics or an...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.13121
更新日期:2015-06-01 00:00:00
abstract::1. The potential influences of nitric oxide (NO) and prostaglandins on the renal effects of angiotensin II (Ang II) have been investigated in the captopril-treated anaesthetized rat by examining the effect of indomethacin or the NO synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME), on the renal respo...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0702003
更新日期:1998-08-01 00:00:00
abstract::1. The noradrenaline concentration in the lung was less than 0.5 mug/g in eight animal species.2. In the cat, dog, rabbit and goat, tyramine produced a fall in pulmonary resistance, which was reduced by the administration of either reserpine or cocaine. Although an infusion of noradrenaline increased the content of th...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1970.tb08525.x
更新日期:1970-02-01 00:00:00
abstract::A dispersed rat anterior pituitary cell system has been used to investigate the effects of cyproheptadine and metergoline on prolactin secretion. Both drugs were potent inhibitors of prolactin secretion. However, the inhibition was not antagonized by either 5-hydroxytryptamine or a variety of dopamine antagonists. We ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1980.tb10896.x
更新日期:1980-09-01 00:00:00
abstract::The metabolism and efficacy of 5-fluorouracil (FUra) and other fluorinated pyrimidine (FP) derivatives have been intensively investigated for over fifty years. FUra and its antimetabolites can be incorporated at RNA- and DNA-levels, with RNA level incorporation provoking toxic responses in human normal tissue, and DNA...
journal_title:British journal of pharmacology
pub_type: 杂志文章,评审
doi:10.1111/j.1476-5381.2009.00423.x
更新日期:2009-10-01 00:00:00
abstract:BACKGROUND AND PURPOSE:The chemokine receptor CXCR3 directs migration of T-cells in response to the ligands CXCL9/Mig, CXCL10/IP-10 and CXCL11/I-TAC. Both ligands and receptors are implicated in the pathogenesis of inflammatory disorders, including atherosclerosis and rheumatoid arthritis. Here, we describe the molecul...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2011.01660.x
更新日期:2012-06-01 00:00:00
abstract::1. Effects of KC399, an opener of ATP-sensitive K+ channels were investigated on membrane potential, isometric force and intracellular Ca2+ ([Ca2+]i) mobilization induced by acetylcholine (ACh) in smooth muscle from the rabbit trachea. 2. In these smooth muscle cells, ACh (0.1 and 1 microM) depolarized the membrane in...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1995.tb16642.x
更新日期:1995-08-01 00:00:00
abstract::Optimum assay conditions for the association of [3H]-para-tyramine [( 3H]-pTA) with rat brain membranes were characterized, and a saturable, reversible, drug-specific, and high affinity binding mechanism for this trace amine was revealed. The binding capacity (Bmax) for [3H]-pTA in the corpus striatum was approximatel...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1986.tb11116.x
更新日期:1986-09-01 00:00:00
abstract::In dog trachea in situ, perfused arterially with blood, isoprenaline, glyceryl trinitrate and N-nitroso-N-morpholinoamino-acetonitrile (SIN-1A) given intra-arterially, decreased tracheal tone which had been elevated by neostigmine and increased tracheal blood flow. Glyceryl trinitrate and SIN-1A were more effective on...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1981.tb16764.x
更新日期:1981-05-01 00:00:00
abstract::1 The D3 dopamine receptor presumably activates Gi/Go subtypes of G-proteins, like the structurally analogous D2 receptor, but its signalling targets have not been clearly established due to weak functional signals from cloned receptors as heterologously expressed in mostly non-neuronal cell lines. 2 In this study, re...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0702905
更新日期:1999-11-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Catechol-O-methyltransferase (COMT) inhibitors are used in Parkinson's disease in which pain is an important symptom. COMT polymorphisms modulate pain and opioid analgesia in humans. In rats, COMT inhibitors have been shown to be pro-nociceptive in acute pain models, but also to attenuate allodyn...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2010.00999.x
更新日期:2010-12-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Increased level of very low-density lipoprotein (VLDL) is a key feature of the metabolic syndrome and is associated with cardiovascular diseases. PPAR-δ agonists play a protective role in lipid metabolism and vascular function. In this study, we aimed to investigate the role of PPAR-δ in the upta...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.13160
更新日期:2015-08-01 00:00:00
abstract:BACKGROUND AND PURPOSE:3,4-Methylenedioxymethamphetamine (MDMA or 'Ecstasy') is a worldwide major drug of abuse known to elicit neurotoxic effects. The mechanisms underlying the neurotoxic effects of MDMA are not clear at present, but the metabolism of dopamine and 5-HT by monoamine oxidase (MAO), as well as the hepati...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2011.01453.x
更新日期:2012-02-01 00:00:00
abstract::1. The role of adrenal hormones in the regulation of the systemic and local production of tumour necrosis factor (TNF alpha) was examined in male Balb/c mice. 2. Intraperitoneal injection of 0.3 mg E. coli lipopolysaccharide (LPS, 0111:B4) led to high levels of circulating TNF alpha without stimulating TNF alpha produ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1996.tb15317.x
更新日期:1996-04-01 00:00:00
abstract::1 The actions of prostaglandin F2 alpha (PGF2 alpha) and noradrenaline on contraction and 45Ca exchange have been studied in rat mesenteric arteries. 2 PGF2 alpha and noradrenaline contracted rat isolated mesenteric artery preparations to about the same extent. The PGF2 alpha-stimulated contractions, unlike those prod...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1982.tb08777.x
更新日期:1982-01-01 00:00:00
abstract::The molecular mechanisms involved in veratridine-induced chromaffin cell death have been explored. We have found that exposure to veratridine (30 microM, 1 h) produces a delayed cellular death that reaches 55% of the cells 24 h after veratridine exposure. This death has the features of apoptosis as DNA fragmentation c...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0703451
更新日期:2000-08-01 00:00:00
abstract::1. The present study was undertaken to investigate the effect of Delta9-tetrahydrocannabinol (Delta9-THC) and possible serotoninergic involvement on the extracellular level of dopamine (DA) in the striatum using microdialysis in conscious, freely-moving rats. 2. A dose-dependent increase in striatal DA release occurre...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0702753
更新日期:1999-09-01 00:00:00
abstract::The effect of fluoxetine on uptake of 5-hydroxytryptamine (5-HT) by enteric 5-hydroxytryptaminergic neurones has been analyzed in order to compare further these neurones with 5-HT neurones of the CNS. In addition, the effects of fluoxetine and chlorimipramine on efflux of [3H]-5-HT from the myenteric plexus were also ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1979.tb16089.x
更新日期:1979-05-01 00:00:00
abstract::The interaction between nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) was investigated in isolated circular smooth muscle cells and strips of the guinea-pig gastric fundus. VIP induced a concentration-dependent inhibition of carbachol-induced contraction in smooth muscle cells with a maximum at 10(-6) ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0703089
更新日期:2000-02-01 00:00:00
abstract::Anthracyclines can cause cumulative dose-related cardiotoxicity characterized by changes in Ca(2+) metabolism, including dysfunction of the sacroplasmic reticulum (SR) and decreased expression of Ca(2+)-handling proteins, such as the ryanodine receptor (RyR2). In this study, we examined the effect of dexrazoxane (ICRF...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0703538
更新日期:2000-09-01 00:00:00
abstract::1. Bepridil (BPD) is a pharmacological compound able to bind to the Ca2+ sensor protein troponin C (TnC), which triggers skeletal muscle contraction upon Ca2+-binding. BPD can thereby modulate the Ca2+-affinity of this protein. 2. The Ca2+-sensitizing action of bepridil was investigated on slow and fast isoforms of Tn...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0702820
更新日期:1999-10-01 00:00:00
abstract::1 alpha-Monofluoromethyldopa (MFMD, RMI 71963), a potent and selective enzyme-activated irreversible inhibitor of aromatic L-amino acid decarboxylase produces a substantial and long-lasting decrease in the catecholamine content of mouse brain, heart and kidney. 2 Single doses of MFMD reduce the 5-hydroxytryptamine con...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1980.tb09776.x
更新日期:1980-12-01 00:00:00
abstract::1. ICI D7114 is a novel, beta-adrenoceptor agonist which stimulates whole body oxygen consumption in conscious rats, cats and dogs and brown adipose tissue (BAT) activity in conscious rats. Treatment of rats with ICI D7114 stimulated oxygen consumption (ED50, 0.04 mg kg-1, p.o.) and BAT mitochondrial guanosine diphosp...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1991.tb12391.x
更新日期:1991-09-01 00:00:00
abstract::The role of nitric oxide (NO) in striatal dopamine release has been controversial. Most NO synthase inhibitors affect more than one isoform of the enzyme and exert vasoconstrictor effects which may also affect striatal dopamine function. We now report on the effect of a soluble monosodium salt of the selective brain N...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1995.tb13219.x
更新日期:1995-01-01 00:00:00
abstract::1. Sarcolemmal membranes were isolated from normal and from denervated muscles and the specific binding of [125I]-alpha-bungarotoxin to the membranes was determined. 2. Cytosol prepared from either slow (soleus) or fast (extensor digitorum longus) muscle increased the toxin binding. Similar effects were seen with cyto...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1988.tb11611.x
更新日期:1988-07-01 00:00:00
abstract::Cyclic adenosine 3',5'-monophosphage (cyclic AMP) levels in guinea-pig tracheal rings increased on incubation with the vasoactive intestinal peptide (VIP). The effect was potentiated by the addition of theophylline. The results suggest that the tracheo-bronchial relaxant action of VIP may be mediated by stimulation of...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1978.tb08471.x
更新日期:1978-03-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Orally administered withanoside IV (a compound isolated from the roots of Withania somnifera) improved memory deficits in mice with a model of Alzheimer's disease induced by the amyloid peptide Abeta(25-35). Sominone, an aglycone of withanoside IV, was identified as an active metabolite after ora...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2009.00313.x
更新日期:2009-08-01 00:00:00
abstract::1. Heat stress (HS) is known to protect against myocardial ischaemia-reperfusion injury by improving mechanical dysfunction and decreasing necrosis. However, the mechanisms responsible for this form of cardioprotection remain to be elucidated. ATP-sensitive potassium (K(ATP)) channels have been shown to be involved in...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0701710
更新日期:1998-03-01 00:00:00
abstract::1 The effects of purported prostaglandin synthesis inhibitors on steroid and prostaglandin (E and F) release from trypsin-dispersed cat adrenocortical cells were investigated. 2 Low indomethacin concentrations potentiated adrenocorticotrophin (ACTH)-evoked prostaglandin and steroid release, whereas higher concentratio...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1976.tb07477.x
更新日期:1976-06-01 00:00:00