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1.
Yingmin Zhu Yungang Lu Chunrong Qu Melissa Miller Jinbin Tian Dhananjay P Thakur Jinmei Zhu Zixin Deng Xianming Hu Meng Wu Owen B McManus Min Li Xuechuan Hong Michael X Zhu Huai-Rong Luo 《British journal of pharmacology》2015,172(14):3495-3509
Background and Purpose
Transient receptor potential canonical (TRPC) channels play important roles in a broad array of physiological functions and are involved in various diseases. However, due to a lack of potent subtype-specific inhibitors the exact roles of TRPC channels in physiological and pathophysiological conditions have not been elucidated.Experimental Approach
Using fluorescence membrane potential and Ca2+ assays and electrophysiological recordings, we characterized new 2-aminobenzimidazole-based small molecule inhibitors of TRPC4 and TRPC5 channels identified from cell-based fluorescence high-throughput screening.Key Results
The original compound, M084, was a potent inhibitor of both TRPC4 and TRPC5, but was also a weak inhibitor of TRPC3. Structural modifications of the lead compound resulted in the identification of analogues with improved potency and selectivity for TRPC4 and TRPC5 channels. The aminobenzimidazole derivatives rapidly inhibited the TRPC4- and TRPC5-mediated currents when applied from the extracellular side and this inhibition was independent of the mode of activation of these channels. The compounds effectively blocked the plateau potential mediated by TRPC4-containing channels in mouse lateral septal neurons, but did not affect the activity of heterologously expressed TRPA1, TRPM8, TRPV1 or TRPV3 channels or that of the native voltage-gated Na+, K+ and Ca2+ channels in dissociated neurons.Conclusions and Implications
The TRPC4/C5-selective inhibitors developed here represent novel and useful pharmaceutical tools for investigation of physiological and pathophysiological functions of TRPC4/C5 channels.Tables of LinksTARGETS | ||
---|---|---|
GPCRsa | Ion channelsb | |
μ receptor | TRPA1 | TRPM8 |
5-HT1A receptor | TRPC1 | TRPV1 |
M2 receptor | TRPC2 | TRPV3 |
M3 receptor | TRPC3 | Voltage-gated Ca2+ channels |
M5 receptor | TRPC4 | Voltage-gated K+ channels |
TRPC5 | Voltage-gated Na+ channels | |
TRPC6 | ||
TRPC7 |
LIGANDS | |
---|---|
2-APB | Flufenamic acid (FFA) |
5-HT | Menthol |
Capsaicin | ML204 |
Carbachol (CCh) | Riluzole |
DAMGO | SKF96365 |
DHPG |
2.
TRPC6 regulates cell cycle progression by modulating membrane potential in bone marrow stromal cells
Background and Purpose
Ca2+ influx is important for cell cycle progression, but the mechanisms involved seem to vary. We investigated the potential roles of transient receptor potential (TRP) channels and store-operated Ca2+ entry (SOCE)-related molecules STIM (stromal interaction molecule)/Orai in the cell cycle progression of rat bone marrow stromal cells (BMSCs), a reliable therapeutic resource for regenerative medicine.Experimental Approach
PCR and immunoblot analyses were used to examine mRNA and protein levels, fluorescence imaging and patch clamping for Ca2+ influx and membrane potential measurements, and flow cytometry for cell cycle analysis.Key Results
Cell cycle synchronization of BMSCs revealed S phase-specific enhancement of TRPC1, STIM and Orai mRNA and protein expression. In contrast, TRPC6 expression decreased in the S phase and increased in the G1 phase. Resting membrane potential (RMP) of BMSCs was most negative and positive in the S and G1 phases, respectively, and was accompanied by an enhancement and attenuation of SOCE respectively. Chemically depolarizing/hyperpolarizing the membrane erased these differences in SOCE magnitude during the cell cycle. siRNA knockdown of TRPC6 produced a negative shift in RMP, increased SOCE and caused redistribution of BMSCs with increased populations in the S and G2/M phases and accumulation of cyclins A2 and B1. A low concentration of Gd3+ (1 μM) suppressed BMSC proliferation at its concentration to inhibit SOC channels relatively specifically.Conclusions and Implications
TRPC6, by changing the membrane potential, plays a pivotal role in controlling the SOCE magnitude, which is critical for cell cycle progression of BMSCs. This finding provides a new therapeutic strategy for regulating BMSC proliferation.Table of LinksTARGETS | LIGANDS |
---|---|
Akt (PKB) | Cyclopiazonic acid |
CDK | 5-fluorouracil |
M2 receptor | Gd3+ |
TRPC1 | OAG |
TRPC6 | Thymidine |
TRPM5 |
3.
Ana Miju?kovi? Aleksandra Nikoli? Koki? Zorana Ore??anin Du?i? Marija Slavi? Mihajlo B Spasi? Du?ko Blagojevi? 《British journal of pharmacology》2015,172(14):3671-3686
Background and Purpose
Hydrogen sulphide reduces uterine contractility and is of potential interest as a treatment for uterine disorders. The aim of this study was to explore the mechanism of sodium sulphide (Na2S)-induced relaxation of rat uterus, investigate the importance of redox effects and ion channel-mediated mechanisms, and any interactions between these two mechanisms.Experimental Approach
Organ bath studies were employed to assess the pharmacological effects of Na2S in uterine strips by exposing them to Na2S with or without Cl− channel blockers (DIDS, NFA, IAA-94, T16Ainh-A01, TA), raised KCl (15 and 75 mM), K+ channel inhibitors (glibenclamide, TEA, 4-AP), L-type Ca2+ channel activator (S-Bay K 8644), propranolol and methylene blue. The activities of antioxidant enzymes were measured in homogenates of treated uteri. The expression of bestrophin channel 1 (BEST-1) was determined by Western blotting and RT-PCR.Key Results
Na2S caused concentration-dependent reversible relaxation of spontaneously active and calcium-treated uteri, affecting both amplitude and frequency of contractions. Uteri exposed to 75 mM KCl were less sensitive to Na2S compared with uteri in 15 mM KCl. Na2S-induced relaxations were abolished by DIDS, but unaffected by other modulators or by the absence of extracellular HCO3−, suggesting the involvement of chloride ion channels. Na2S in combination with different modulators provoked specific changes in the anti-oxidant profiles of uteri. The expression of BEST-1, both mRNA and protein, was demonstrated in rat uteri.Conclusions and Implications
The relaxant effects of Na2S in rat uteri are mediated mainly via a DIDS-sensitive Cl−-pathway. Components of the relaxation are redox- and Ca2+-dependent.Tables of LinksTARGETS | |
---|---|
GPCRsa,2006 | Transportersc,2006 |
β-adrenoceptor | Cl-/HCO3- exchanger |
Ion channelsb,2006 | Enzymesd,2006 |
CaCC | Cystathionine β-synthase |
KATP channels | Cystathionine γ-lyase |
Kv channels | GR |
TMEM16 channel | Guanylyl cyclase |
LIGANDS | |
---|---|
4-AP | NaHS |
Adrenaline | Niflumic acid (NFA) |
CGRP | Nitric oxide (NO) |
DIDS | Propranolol |
Glibenclamide | S-Bay K 8644 |
H2O2 | Tannic acid (TA) |
IAA-94 | TEA |
4.
Dominika Pa?esová Barbora Volfová Kate?ina ?ervená Lucie Hejnová Ji?í Novotny Zdeňka Bendová 《British journal of pharmacology》2015,172(14):3638-3649
Background and Purpose
Opioids affect the circadian clock and may change the timing of many physiological processes. This study was undertaken to investigate the daily changes in sensitivity of the circadian pacemaker to an analgesic dose of morphine, and to uncover a possible interplay between circadian and opioid signalling.Experimental Approach
A time-dependent effect of morphine (1 mg·kg−1, i.p.) applied either during the day or during the early night was followed, and the levels of phosphorylated ERK1/2, GSK3β, c-Fos and Per genes were assessed by immunohistochemistry and in situ hybridization. The effect of morphine pretreatment on light-induced pERK and c-Fos was examined, and day/night difference in activity of opioid receptors was evaluated by [35S]-GTPγS binding assay.Key Results
Morphine stimulated a rise in pERK1/2 and pGSK3β levels in the suprachiasmatic nucleus (SCN) when applied during the day but significantly reduced both kinases when applied during the night. Morphine at night transiently induced Period1 but not Period2 in the SCN and did not attenuate the light-induced level of pERK1/2 and c-Fos in the SCN. The activity of all three principal opioid receptors was high during the day but decreased significantly at night, except for the δ receptor. Finally, we demonstrated daily profiles of pERK1/2 and pGSK3β levels in the rat ventrolateral and dorsomedial SCN.Conclusions and Implications
Our data suggest that the phase-shifting effect of opioids may be mediated via post-translational modification of clock proteins by means of activated ERK1/2 and GSK3β.Tables of LinksTARGETS | |
---|---|
GPCRsa1997 | Enzymesc1997 |
δ receptor | Akt (PKB) |
κ receptor | Clock |
μ receptor | ERK1/2 |
Nuclear hormone receptorsb1997 | GSK3β |
Rev-Erb-α |
LIGANDS | |
---|---|
Arginine vasopressin | GDP |
cAMP | GTPγS |
DADLE | Morphine |
DAMGO | Neuropeptide Y |
Enkephalin | Thiopental |
GABA | U-50488 |
Gastrin | UTP |
5.
S M Krishnan C G Sobey E Latz A Mansell G R Drummond 《British journal of pharmacology》2014,171(24):5589-5602
Chronic inflammation in the kidneys and vascular wall is a major contributor to hypertension. However, the stimuli and cellular mechanisms responsible for such inflammatory responses remain poorly defined. Inflammasomes are crucial initiators of sterile inflammation in other diseases such as rheumatoid arthritis and gout. These pattern recognition receptors detect host-derived danger-associated molecular patterns (DAMPs), such as microcrystals and reactive oxygen species, and respond by inducing activation of caspase-1. Caspase-1 then processes the cytokines pro-IL-1β and pro-IL-18 into their active forms thus triggering inflammation. While IL-1β and IL-18 are known to be elevated in hypertensive patients, no studies have examined whether this occurs downstream of inflammasome activation or whether inhibition of inflammasome and/or IL-1β/IL-18 signalling prevents hypertension. In this review, we will discuss some known actions of IL-1β and IL-18 on leukocyte and vessel wall function that could potentially underlie a prohypertensive role for these cytokines. We will describe the major classes of inflammasome-activating DAMPs and present evidence that at least some of these are elevated in the setting of hypertension. Finally, we will provide information on drugs that are currently used to inhibit inflammasome/IL-1β/IL-18 signalling and how these might ultimately be used as therapeutic agents for the clinical management of hypertension.Tables of Links
Open in a separate windowThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 (a,b,c,d Alexander et al., 2013a,b,c,d,,,).
Open in a separate window 相似文献
TARGETS | |
---|---|
Catalytic receptorsa2013a | Enzymesd2013a |
IL-1 receptor | Caspase-1 |
IL-1 decoy receptor (IL-1RII) | HMG CoA reductase |
IL-18 receptor | Endothelial NOS |
GPCRsb2013a | Inducible NOS |
Angiotensin AT1 receptor | |
CCR2 | |
Ligand-gated ion channelsc2013a | |
P2X7 receptor |
LIGANDS |
---|
A-438079 |
Anakinra |
Angiotensin II |
Canakinumab |
IL-1Ra |
IL-18 |
IL-33 |
Simvastatin |
TNF-α |
6.
Chunling Yan Yongjie Yang Kenji Saito Pingwen Xu Chunmei Wang Antentor Othrell Hinton Jr Xiaofeng Yan Qi Wu Qingchun Tong Joel K Elmquist Makoto Fukuda Yong Xu 《British journal of pharmacology》2015,172(14):3510-3521
Background and Purpose
Most forms of human obesity are characterized by impaired leptin sensitivity and, therefore, the effectiveness of anti-obesity leptin therapy in these leptin-resistant obese patients is marginal. Hence, the development of strategies to increase leptin sensitivity is of high priority in the field of obesity research.Experimental Approach
We first examined the effects of co-administration of leptin and meta-chlorophenylpiperazine (mCPP), an agonist of 5-HT2C and 5-HT1B receptors, on energy balance in leptin-resistant diet-induced obese (DIO) mice. We further assessed leptin-induced phosphorylation of the STAT-3 (pSTAT3) in various brain regions of DIO mice pretreated with mCPP or in mice genetically lacking 5-HT2C receptors.Results
Co-administration of mCPP with leptin had an additive effect on reducing body weight in DIO mice. Furthermore, mCPP pretreatment in DIO mice enhanced leptin-induced pSTAT3 in the arcuate nucleus, the ventromedial hypothalamic nucleus, and the ventral premammillary nucleus. Finally, deletion of 5-HT2C receptors significantly blunted leptin-induced pSTAT3 in these same hypothalamic regions.Conclusions and Implications
Our study provides evidence that drugs, which activate 5-HT2C receptors, could function as leptin sensitizers and be used in combination with leptin to provide additional weight loss in DIO.Tables of LinksTARGETS | |
---|---|
GPCRsa | Catalytic receptorsb |
5-HT1B receptor | Leptin receptor |
5-HT2C receptor | Enzymesc |
Melanocortin 4 receptor | JAK2 |
LIGANDS | |
---|---|
5-HT | Leptin |
Agouti-related peptide | Lorcaserin |
Amylin | Meta-chlorophenylpiperazine |
Glycine | Neuropeptide Y |
H2O2 | POMC |
Isoflurane | Sibutramine |
7.
The history of ketamine and phencyclidine from their development as potential clinical anaesthetics through drugs of abuse and animal models of schizophrenia to potential rapidly acting antidepressants is reviewed. The discovery in 1983 of the NMDA receptor antagonist property of ketamine and phencyclidine was a key step to understanding their pharmacology, including their psychotomimetic effects in man. This review describes the historical context and the course of that discovery and its expansion into other hallucinatory drugs. The relevance of these findings to modern hypotheses of schizophrenia and the implications for drug discovery are reviewed. The findings of the rapidly acting antidepressant effects of ketamine in man are discussed in relation to other glutamatergic mechanisms.Tables of Links
Open in a separate window
Open in a separate windowThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14a,b,c,dAlexander et al., 2013a,b,c,d,,,). 相似文献
TARGETS | |
---|---|
GPCRsa | Ligand-gated ion channelsb |
κ receptor | AMPA receptors |
μ receptor | GluN2A |
ACh receptors (muscarinic) | GluN2B |
Cannabinoid receptors | GluN2C |
D2 receptor | GluN2D |
Metabotrophic glutamate receptors | Kainate receptors |
Enzymesd | NMDA receptors |
Cholinesterases | Nicotinic ACh receptors |
GAD-67 | |
GSK-3 | Ion channelc |
mTOR | HCN1 |
PKB (Akt) |
LIGANDS | ||
---|---|---|
5-HT | Dopamine | Morphine |
ACh | Ethylketocyclazocine | Naloxone |
AMPA | HA-966 | NMDA |
Amphetamine | Ifenprodil | Noradrenaline |
Bicuculline | Kainate | Pentazocine |
Chlorpromazine | Ketamine (CI-581) | Phencyclidine |
Cyclazocine | Levorphanol | Pregnenolone |
D-AP5 | LSD | Quisqualate |
Dextromethorphan | Memantine | U50488H |
Dizocilpine (MK-801) |
8.
J Y Moon D H Roh S Y Yoon S R Choi S G Kwon H S Choi S Y Kang H J Han A J Beitz S B Oh J H Lee 《British journal of pharmacology》2014,171(24):5881-5897
Background and Purpose
Spinal astrocytes have emerged as important mechanistic contributors to the genesis of mechanical allodynia (MA) in neuropathic pain. We recently demonstrated that the spinal sigma non-opioid intracellular receptor 1 (σ1 receptor) modulates p38 MAPK phosphorylation (p-p38), which plays a critical role in the induction of MA in neuropathic rats. However, the histological and physiological relationships among σ1, p-p38 and astrocyte activation is unclear.Experimental Approach
We investigated: (i) the precise location of σ1 receptors and p-p38 in spinal dorsal horn; (ii) whether the inhibition of σ1 receptors or p38 modulates chronic constriction injury (CCI)-induced astrocyte activation; and (iii) whether this modulation of astrocyte activity is associated with MA development in CCI mice.Key Results
The expression of σ1 receptors was significantly increased in astrocytes on day 3 following CCI surgery. Sustained intrathecal treatment with the σ1 antagonist, BD-1047, attenuated CCI-induced increase in GFAP-immunoreactive astrocytes, and the treatment combined with fluorocitrate, an astrocyte metabolic inhibitor, synergistically reduced the development of MA, but not thermal hyperalgesia. The number of p-p38-ir astrocytes and neurons, but not microglia was significantly increased. Interestingly, intrathecal BD-1047 attenuated the expression of p-p38 selectively in astrocytes but not in neurons. Moreover, intrathecal treatment with a p38 inhibitor attenuated the GFAP expression, and this treatment combined with fluorocitrate synergistically blocked the induction of MA.Conclusions and Implications
Spinal σ1 receptors are localized in astrocytes and blockade of σ1 receptors inhibits the pathological activation of astrocytes via modulation of p-p38, which ultimately prevents the development of MA in neuropathic mice.Tables of LinksTARGETS | |
---|---|
Other protein targetsa,2008 | Enzymesc,2008 |
Sigma non-opioid intracellular receptor 1 | p38 MAPK |
Ligand-gated ion channelsb,2008 | |
GluN1 |
LIGANDS |
---|
BD-1047 |
SB203580 |
9.
Terry Kenakin 《British journal of pharmacology》2015,172(17):4238-4253
This review is based on the JR Vane Medal Lecture presented at the BPS Winter Meeting in December 2014 by T. Kenakin. A recording of the lecture is included as supporting information and can also be viewed online here: https://www.youtube.com/watch?v=xrP81AQ8l-8. Pharmacological models used to describe drug agonism and antagonism have evolved over the past 20 years from a parsimonious model describing single active and inactive receptor states to models of multiconformational receptor systems modified by ligand conformational selection. These latter models describe the observed, presently underexploited, pharmacological mechanism of ligand-directed biased signalling. Biased signals can be quantified with transduction coefficients (ΔΔLog(τ/KA) values), a scale grounded in the Black/Leff operational model; this enables the optimization of biased profiles through medicinal chemistry. The past decades have also brought the availability of new technologies to measure multiple functional effects mediated by seven transmembrane receptors. These have confirmed that drugs can have many efficacies, which may be collaterally linked, that is there is no linear sequence of activities required. In addition, new functional screening assays have introduced increasing numbers of allosteric ligands into drug discovery. These molecules are permissive (they do not necessarily preclude endogenous signalling in vivo); therefore, they may allow better fine tuning of pathological physiology. The permissive quality of allosteric ligands can also change the quality of endogenous signalling efficacy (‘induced bias’) as well as the quantity of signal; in this regard, indices related to ΔΔLog(τ/KA) values (namely ΔLog(αβ) values) can be used to quantify these effects for optimization in the drug discovery process. All of these added scales of drug activity will, hopefully, allow better targeting of candidate molecules towards therapies.Tables of Links
Open in a separate windowOpen in a separate windowThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14a,bAlexander et al., 2013a,b,). 相似文献
TARGETS | |
---|---|
GPCRsa | Enzymesb |
β2-adrenoceptor | Adenylate cyclase |
μ receptor | ERK |
CRF2 receptor | |
CT receptor | |
D2 receptor | |
GLP-1 receptor | |
mGlu5 receptor | |
NK2 receptor | |
PACAP receptor |
10.
Xiao-Yi Zeng Hao Wang Fang Bai Xiu Zhou Song-Pei Li Lu-Ping Ren Ruo-Qiong Sun Charlie C L Xue Hua-Liang Jiang Li-Hong Hu Ji-Ming Ye 《British journal of pharmacology》2015,172(17):4303-4318
Background and Purpose
Matrine is a small molecule drug used in humans for the treatment of chronic viral infections and tumours in the liver with little adverse effects. The present study investigated its therapeutic efficacy for insulin resistance and hepatic steatosis in high-fat-fed mice.Experimental Approach
C57BL/J6 mice were fed a chow or high-fat diet for 10 weeks and then treated with matrine or metformin for 4 weeks. The effects on lipid metabolism and glucose tolerance were evaluated.Key Results
Our results first showed that matrine reduced glucose intolerance and plasma insulin level, hepatic triglyceride content and adiposity in high-fat-fed mice without affecting caloric intake. This reduction in hepatosteatosis was attributed to suppressed lipid synthesis and increased fatty acid oxidation. In contrast to metformin, matrine neither suppressed mitochondrial respiration nor activated AMPK in the liver. A computational docking simulation revealed HSP90, a negative regulator of HSP72, as a potential binding target of matrine. Consistent with the simulation results, matrine, but not metformin, increased the hepatic protein level of HSP72 and this effect was inversely correlated with both liver triglyceride level and glucose intolerance.Conclusions and Implications
Taken together, these results indicate that matrine may be used for the treatment of type 2 diabetes and hepatic steatosis, and the molecular action of this hepatoprotective drug involves the activation of HSP72 in the liver.Tables of LinksTARGETS | |
---|---|
Nuclear hormone receptorsa | Transportersb |
PPARα | UCP2 |
Enzymesc | |
ACC | GSK3β |
AMPK | IKKα |
AST | IKKβ |
ERK1 | JNK |
ERK2 | PKCε |
FAS | |
Other protein targets | |
α-tubulin | HSP72 |
LIGANDS | |
---|---|
Adiponectin | Leptin |
IL-1β | Metformin |
IL-6 (HSF1) | Palmitate |
Insulin | TNFα |
11.
Dieniffer Peixoto-Neves Qian Wang Jose H Leal-Cardoso Luciana V Rossoni Jonathan H Jaggar 《British journal of pharmacology》2015,172(14):3484-3494
Background and Purpose
Eugenol, a vanilloid molecule found in some dietary plants, relaxes vasculature in part via an endothelium-dependent process; however, the mechanisms involved are unclear. Here, we investigated the endothelial cell-mediated mechanism by which eugenol modulates rat mesenteric artery contractility and systemic BP.Experimental Approach
The isometric tension of rat mesenteric arteries (size 200–300 μm) was measured using wire myography; non-selective cation currents (ICat) were recorded in endothelial cells using patch clamp electrophysiology. Mean arterial pressure (MAP) and heart rate (HR) were determined in anaesthetized rats.Key Results
Eugenol relaxed endothelium-intact arteries in a concentration-dependent manner and this effect was attenuated by endothelium denudation. L-NAME, a NOS inhibitor, a combination of TRAM-34 and apamin, selective blockers of intermediate and small conductance Ca2+-activated K+ channels, respectively, and HC-067047, a TRPV4 channel inhibitor, but not indomethacin, a COX inhibitor, reduced eugenol-induced relaxation in endothelium-intact arteries. Eugenol activated HC-067047-sensitive ICat in mesenteric artery endothelial cells. Short interfering RNA (siRNA)-mediated TRPV4 knockdown abolished eugenol-induced ICat activation. An i.v. injection of eugenol caused an immediate, transient reduction in both MAP and HR, which was followed by prolonged, sustained hypotension in anaesthetized rats. This sustained hypotension was blocked by HC-067047.Conclusions and Implications
Eugenol activates TRPV4 channels in mesenteric artery endothelial cells, leading to vasorelaxation, and reduces systemic BP in vivo. Eugenol may be therapeutically useful as an antihypertensive agent and is a viable molecular candidate from which to develop second-generation TRPV4 channel activators that reduce BP.Tables of LinksTARGETS | |
---|---|
GPCRsa | Ion channelsb |
TXA2 (TP) receptor | BK (KCa 1.1) channel |
Enzymesc | IKCa (KCa 3.1) channel |
COX | SKCa (KCa 2.1) channel |
NOS | TMEM16A (CaCC) |
TRPV4 |
LIGANDS | ||
---|---|---|
ACh | GSK1016790A | Phenylephrine |
Apamin | HC-067047 | PGI2 |
Capsaicin | Indomethacin | TRAM-34 |
Eugenol | L-NAME | U46619 |
Nitric oxide (NO) |
12.
Shingo Takatori Kazuhiro Hirai Shuichiro Ozaki Panot Tangsucharit Satoko Fukushima-Miyashita Mitsuhiro Goda Narumi Hashikawa-Hobara Nobufumi Ono Hiromu Kawasaki 《British journal of pharmacology》2014,171(24):5743-5756
Background and Purpose
Previous studies have demonstrated that nicotine releases protons from adrenergic nerves via stimulation of nicotinic ACh receptors and activates transient receptor potential vanilloid-1 (TRPV1) receptors located on calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves, resulting in vasodilatation. The present study investigated whether perivascular nerves release protons, which modulate axon-axonal neurotransmission.Experiment Approach
Perfusion pressure and pH levels of perfusate in rat-perfused mesenteric vascular beds without endothelium were measured with a pressure transducer and a pH meter respectively.Key Results
Periarterial nerve stimulation (PNS) initially induced vasoconstriction, which was followed by long-lasting vasodilatation and decreased pH levels in the perfusate. Cold-storage denervation of the preparation abolished the decreased pH and vascular responses to PNS. The adrenergic neuron blocker guanethidine inhibited PNS-induced vasoconstriction and effects on pH, but not PNS-induced vasodilatation. Capsaicin (CGRP depletor), capsazepine and ruthenium red (TRPV1 inhibitors) attenuated the PNS-induced decrease in pH and vasodilatation. In denuded preparations, ACh caused long-lasting vasodilatation and lowered pH; these effects were inhibited by capsaicin pretreatment and atropine, but not by guanethidine or mecamylamine. Capsaicin injection induced vasodilatation and a reduction in pH, which were abolished by ruthenium red. The use of a fluorescent pH indicator demonstrated that application of nicotine, ACh and capsaicin outside small mesenteric arteries reduced perivascular pH levels and these effects were abolished in a Ca2+-free medium.Conclusion and Implication
These results suggest that protons are released from perivascular adrenergic and CGRPergic nerves upon PNS and these protons modulate transmission in CGRPergic nerves.Tables of LinksTargets |
---|
GPCRs |
α1-adrenoceptor |
Muscarinic ACh receptor |
CGRP receptor |
Ligand-gated ion channels |
Nicotinic ACh receptor |
Ion channels |
TRPV1 channel |
LIGANDS | |
---|---|
ACh | Mecamylamine |
Atropine | Methoxamine |
Capsaicin | Neuropeptide Y |
Capsazepine | Nicotine |
CGRP | Nitric oxide (NO) |
Guanethidine | Noradrenaline |
Ruthenium red |
13.
Vinayak S Jamdade Nikunj Sethi Nitin A Mundhe Parveen Kumar Mangala Lahkar Neeraj Sinha 《British journal of pharmacology》2015,172(17):4228-4237
Breast cancer (BC) is the second most common cause of cancer deaths. Triple-negative breast cancer (TNBC) does not show immunohistochemical expression of oestrogen receptors, progesterone receptors or HER2. At present, no suitable treatment option is available for patients with TNBC. This dearth of effective conventional therapies for the treatment of advanced stage breast cancer has provoked the development of novel strategies for the management of patients with TNBC. This review presents recent information associated with different therapeutic options for the treatment of TNBC focusing on promising targets such as the Notch signalling, Wnt/β-catenin and Hedgehog pathways, in addition to EGFR, PARP1, mTOR, TGF-β and angiogenesis inhibitors.Tables of Links
Open in a separate window
Open in a separate windowThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14a,b,cAlexander et al., 2013a,b,c,,). 相似文献
TARGETS | |
---|---|
GPCRsa | Enzymesc |
FZD7 receptor | ADAM |
SMO receptor | ADAM17 |
Catalytic receptorsb | Akt (PKB) |
EGFR | Aspartyl protease |
Fas | GSK3β |
HER2 | mTOR |
TGFBR1 | PARP1 |
VEGFR2 | p70S6kinase |
PKCα | |
SGK1 | |
ULK1 |
LIGANDS | |
---|---|
β-catenin | Lapatinib |
Angiopoietin-1 | LY2157299 |
Angiopoietin-2 | Neratinib |
Cisplatin | Olaparib |
Erlotinib | Rapamycin |
Everolimus | Rucaparib |
Gefitinib | Temsirolimus |
IFN-γ | TGFβ |
IGF-1 | TNF-α |
IL-1α | Veliparib |
IL-1β | Wnt |
IL-2 |
14.
Alexander I Bondarenko 《British journal of pharmacology》2014,171(24):5573-5588
Cannabinoids and their synthetic analogues affect a broad range of physiological functions, including cardiovascular variables. Although direct evidence is still missing, the relaxation of a vast range of vascular beds induced by cannabinoids is believed to involve a still unidentified non-CB1, non-CB2 Gi/o protein-coupled receptor located on endothelial cells, the so called endothelial cannabinoid receptor (eCB receptor). Evidence for the presence of an eCB receptor comes mainly from vascular relaxation studies, which commonly employ pertussis toxin as an indicator for GPCR-mediated signalling. In addition, a pharmacological approach is widely used to attribute the relaxation to eCB receptors. Recent findings have indicated a number of GPCR-independent targets for both agonists and antagonists of the presumed eCB receptor, warranting further investigations and cautious interpretation of the vascular relaxation studies. This review will provide a brief historical overview on the proposed novel eCB receptor, drawing attention to the discrepancies between the studies on the pharmacological profile of the eCB receptor and highlighting the Gi/o protein-independent actions of the eCB receptor inhibitors widely used as selective compounds. As the eCB receptor represents an attractive pharmacological target for a number of cardiovascular abnormalities, defining its molecular identity and the extent of its regulation of vascular function will have important implications for drug discovery. This review highlights the need to re-evaluate this subject in a thoughtful and rigorous fashion. More studies are needed to differentiate Gi/o protein-dependent endothelial cannabinoid signalling from that involving the classical CB1 and CB2 receptors as well as its relevance for pathophysiological conditions.Table of Links
Open in a separate windowThis Table lists key protein targets and ligands in this document, which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 (Alexander et al., 2013a,b,c,d,f,g,,,,,). 相似文献
TARGETS | LIGANDS |
---|---|
5-HT receptor | Abn-CBD |
α1 adrenoceptor | Acetylcholine |
Akt | Anandamide (AEA) |
AT1 receptor | AM251 |
BKCa channels | Apamin |
CaV2.2 | Bradykinin |
CaV3.1 | Cannabidiol |
CaV3.2 | Carbachol |
CaV3.3 | Charybdotoxin |
CB1 receptor | Forskolin |
CB2 receptor | HU-210 |
ERK1/2 | Iberiotoxin |
Glycine receptors | L-NAME |
GPR18 | LPI |
GPR55 | NaGly |
GPR119 | NO |
Ionotropic glutamate receptor | NS1619 |
IP3 receptor | O-1602 |
KCa channels | Oleamide |
M1 muscarinic receptor | Oleoylethanolamide |
M2 muscarinic receptor | Rimonabant (SR141716) |
MAPK | Ryanodine |
Na+/Ca2+ exchanger (NCX) | THC |
NaV channel | WIN55212-2 |
Nicotinic acetylcholine receptors | |
NOS | |
Opioid receptors | |
PI3K | |
PPARγ | |
ROCK | |
TRP channels | |
TRPV channels | |
VEGF receptor |
15.
Danit Mechlovich Tamar Amit Orit Bar-Am Orly Weinreb Moussa B H Youdim 《British journal of pharmacology》2014,171(24):5636-5649
Background and Purpose
Neurodegenerative diseases are now recognized to be multifunctional, whereby a heterogeneous set of reactions acts independently or cooperatively, leading eventually to the demise of neurons. This has led our group to design and synthesize the multifunctional, nontoxic, brain-permeable, iron chelator compound M30 with a range of pharmacological properties. Here, we have characterized the molecular targets of M30 in the brains of animal models of type 2 diabetes mellitus (T2DM).Experimental Approach
Effects of M30 on molecular mechanisms associated with neuroprotection in the CNS were investigated-in the high-fat diet (HFD) and ob/ob transgenic mouse models of T2DM, using real-time PCR and Western blotting analyses. Brain monoamine oxidase (MAO) activity and catecholamine levels, and peripheral glucose tolerance were assayed after treatment in vivo.Key Results
M30 increased cerebral levels of insulin and insulin receptor and phosphorylated-GSK-3β in HFD mice, compared with vehicle-treated HFD mice. In both T2DM mice models, M30 treatment significantly up-regulated cerebral hypoxia-inducible factor (HIF)-1α protein levels and induced the expression of several HIF-1 target genes involved in neuroprotection, glycolysis, neurogenesis, oxidative stress and anti-inflammation. Additionally, M30 inhibited MAO-A and -B activities in the cerebellum. Accordingly, M30 administration significantly reduced brain levels of dopamine metabolites and increased levels of 5-HT and noradrenaline. Glucose tolerance was also improved after M30 treatment in both models of T2DM.Conclusions and Implications
In the brain of HFD and ob/ob transgenic mice, M30 exerted a variety of beneficial neuroprotective regulatory effects that may act synergistically to delay or prevent neurodegenerative processes associated with T2DM.Tables of LinksTARGETS | LIGANDS |
---|---|
GLUT-1, glucose transporter 1 | 5-HT |
GSK-3β, glycogen synthase kinase 3β | Deprenyl (selegiline) |
HO-1, haem oxygenase | Dopamine |
InsR, insulin receptor | Noradrenaline |
Insulin | Rasagiline |
MAO-A, monoamine oxidase A | |
MAO-B, monoamine oxidase B |
16.
C-Y Wu M-W Lin D-C Wu Y-B Huang H-T Huang C-L Chen 《British journal of pharmacology》2014,171(24):5541-5554
Reorganization of the actin cytoskeleton is essential for cell motility and chemotaxis. Actin-binding proteins (ABPs) and membrane lipids, especially phosphoinositides PI(4,5)P2 and PI(3,4,5)P3 are involved in the regulation of this reorganization. At least 15 ABPs have been reported to interact with, or regulated by phosphoinositides (PIPs) whose synthesis is regulated by extracellular signals. Recent studies have uncovered several parallel intracellular signalling pathways that crosstalk in chemotaxing cells. Here, we review the roles of ABPs and phosphoinositides in chemotaxis and cell migration.
Open in a separate windowThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 (a,b,cAlexander et al., 2013a,b,c,,).
Open in a separate window 相似文献
Linked Articles
This article is part of a themed section on Cytoskeleton, Extracellular Matrix, Cell Migration, Wound Healing and Related Topics. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-24Tables of LinksTARGETS |
---|
Enzymesa |
PI3Kγ |
PLCβ2 |
PTEN phosphatase |
SHIP1, (INPP5D) |
GPCRsb |
CCR5 |
CXCR4 |
Ligand-gated ion channelsc |
IP3 receptors |
LIGANDS |
---|
C5a, complement component |
cAMP |
fMLP, formylMet-Leu-Phe |
IL-8 |
IP3, inositol 1,4,5-triphosphate; |
LTB4 |
PI(3,4,5)P3, phosphatidylinositol 3,4,5-triphosphate, PIP3 |
PI(4,5)P2, phosphatidylinositol 4,5-bisphosphate; PIP2 |
17.
Eva Wex Ines Kollak Matthias J Duechs Emmanuel Naline Lutz Wollin Philippe Devillier 《British journal of pharmacology》2015,172(14):3537-3547
Background and Purpose
β2-adrenoceptor agonists are widely used in the management of obstructive airway diseases. Besides their bronchodilatory effect, several studies suggest inhibitory effects on various aspects of inflammation. The aim of our study was to determine the efficacy of the long-acting β2-adrenoceptor agonist olodaterol to inhibit pulmonary inflammation and to elucidate mechanism(s) underlying its anti-inflammatory actions.Experimental Approach
Olodaterol was tested in murine and guinea pig models of cigarette smoke- and LPS-induced lung inflammation. Furthermore, effects of olodaterol on the LPS-induced pro-inflammatory mediator release from human parenchymal explants, CD11b adhesion molecule expression on human granulocytes TNF-α release from human whole blood and on the IL-8-induced migration of human peripheral blood neutrophils were investigated.Key Results
Olodaterol dose-dependently attenuated cell influx and pro-inflammatory mediator release in murine and guinea pig models of pulmonary inflammation. These anti-inflammatory effects were observed at doses relevant to their bronchodilatory efficacy. Mechanistically, olodaterol attenuated pro-inflammatory mediator release from human parenchymal explants and whole blood and reduced expression of CD11b adhesion molecules on granulocytes, but without direct effects on IL-8-induced neutrophil transwell migration.Conclusions and Implications
This is the first evidence for the anti-inflammatory efficacy of a β2-adrenoceptor agonist in models of lung inflammation induced by cigarette smoke. The long-acting β2-adrenoceptor agonist olodaterol attenuated pulmonary inflammation through mechanisms that are separate from direct inhibition of bronchoconstriction. Furthermore, the in vivo data suggest that the anti-inflammatory properties of olodaterol are maintained after repeated dosing for 4 days.Tables of LinksTARGETS |
---|
GPCRsa |
β2-adrenoceptors |
β1-adrenoceptors |
CXCR2 |
Catalytic receptorsb |
CD11b |
Enzymesc |
MMP-9 |
LIGANDS | |
---|---|
ACh | IL-8 |
CCL2 | KC (mouse orthologue of CXCL1) |
CCL4 | LPS |
CGP-20712A | M-CSF-1 |
CXCL9 | Olodaterol |
GM-CSF | TNFα |
ICI-118,551 |
18.
U Taschler T O Eichmann F P W Radner G F Grabner H Wolinski M Storr A Lass R Schicho R Zimmermann 《British journal of pharmacology》2015,172(17):4419-4429
Background and Purpose
Monoglyceride lipase (MGL) degrades 2-arachidonoyl glycerol (2-AG), an endogenous agonist of cannabinoid receptors (CB1/2). Because the CB1 receptor is involved in the control of gut function, we investigated the effects of pharmacological inhibition and genetic deletion of MGL on intestinal motility. Furthermore, we determined whether defective 2-AG degradation affects μ-opioid receptor (μ receptor) signalling, a parallel pathway regulating gut motility.Experimental Approach
Gut motility was investigated by monitoring Evans Blue transit and colonic bead propulsion in response to MGL inhibition and CB1 receptor or μ receptor stimulation. Ileal contractility was investigated by electrical field stimulation. CB1 receptor expression in ileum and colon was assessed by immunohistochemical analyses.Key Results
Pharmacological inhibition of MGL slowed down whole gut transit in a CB1 receptor-dependent manner. Conversely, genetic deletion of MGL did not affect gut transit despite increased 2-AG levels. Notably, MGL deficiency caused complete insensitivity to CB1 receptor agonist-mediated inhibition of whole gut transit and ileal contractility suggesting local desensitization of CB1 receptors. Accordingly, immunohistochemical analyses of myenteric ganglia of MGL-deficient mice revealed that CB1 receptors were trapped in endocytic vesicles. Finally, MGL-deficient mice displayed accelerated colonic propulsion and were hypersensitive to μ receptor agonist-mediated inhibition of colonic motility. This phenotype was reproduced by chronic pharmacological inhibition of MGL.Conclusion and Implications
Constantly elevated 2-AG levels induce severe desensitization of intestinal CB1 receptors and increased sensitivity to μ receptor-mediated inhibition of colonic motility. These changes should be considered when cannabinoid-based drugs are used in the therapy of gastrointestinal diseases.Tables of LinksTARGETS | |
---|---|
GPCRsa | Enzymesb |
μ receptor | FAAH |
CB1 receptor | MGL |
CB2 receptor |
LIGANDS | |
---|---|
2-AG | JZL184 |
ACh | Loperamide |
Arachidonic acid | Salvinorin A |
Bethanechol | WIN55,212-2 |
CP55,940 |
19.
C Norez C Vandebrouck J Bertrand S Noel E Durieu N Oumata H Galons F Antigny A Chatelier P Bois L Meijer F Becq 《British journal of pharmacology》2014,171(21):4831-4849
Background and Purpose
The most common mutation in cystic fibrosis (CF), F508del, causes defects in trafficking, channel gating and endocytosis of the CF transmembrane conductance regulator (CFTR) protein. Because CF is an orphan disease, therapeutic strategies aimed at improving mutant CFTR functions are needed to target the root cause of CF.Experimental Approach
Human CF airway epithelial cells were treated with roscovitine 100 μM for 2 h before CFTR maturation, expression and activity were examined. The mechanism of action of roscovitine was explored by recording the effect of depleting endoplasmic reticulum (ER) Ca2+ on the F508del-CFTR/calnexin interaction and by measuring proteasome activity.Key Results
Of the cyclin-dependent kinase (CDK) inhibitors investigated, roscovitine was found to restore the cell surface expression and defective channel function of F508del-CFTR in human CF airway epithelial cells. Neither olomoucine nor (S)-CR8, two very efficient CDK inhibitors, corrected F508del-CFTR trafficking demonstrating that the correcting effect of roscovitine was independent of CDK inhibition. Competition studies with inhibitors of the ER quality control (ERQC) indicated that roscovitine acts on the calnexin pathway and on the degradation machinery. Roscovitine was shown (i) to partially inhibit the interaction between F508del-CFTR and calnexin by depleting ER Ca2+ and (ii) to directly inhibit the proteasome activity in a Ca2+-independent manner.Conclusions and Implications
Roscovitine is able to correct the defective function of F508del-CFTR by preventing the ability of the ERQC to interact with and degrade F508del-CFTR via two synergistic but CDK-independent mechanisms. Roscovitine has potential as a pharmacological therapy for CF.Table of LinksTARGETS | LIGANDS |
---|---|
CDK1 | 2-APB |
CDK2 | ATP |
CDK5 | Calmodulin |
CDK9 | Curcumin |
CFTR | DIDS |
CK1 | DPC |
CLK3 | Forskolin |
DYRK1A | Genistein |
ERK2 | Glibenclamide |
GSK-3 | HSP90 |
IP3 receptor | KN62 |
KV1.3 | Miglustat |
KV2.1 | NO |
KV4.3 | Roscovitine |
KV11.1 | Sildenafil |
L-type Ca channels | Thapsigargin |
NaV1.5 | Vardenafil |