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1.
D 1- and D 2-types of dopamine receptors are located separately in direct and indirect pathway striatal projection neurons (dSPNs and iSPNs). In comparison, adenosine A 1-type receptors are located in both neuron classes, and adenosine A 2A-type receptors show a preferential expression in iSPNs. Due to their importance for neuronal excitability, Ca 2+-currents have been used as final effectors to see the function of signaling cascades associated with different G protein-coupled receptors. For example, among many other actions, D 1-type receptors increase, while D 2-type receptors decrease neuronal excitability by either enhancing or reducing, respectively, Ca V1 Ca 2+-currents. These actions occur separately in dSPNs and iSPNs. In the case of purinergic signaling, the actions of A 1- and A 2A-receptors have not been compared observing their actions on Ca 2+-channels of SPNs as final effectors. Our hypotheses are that modulation of Ca 2+-currents by A 1-receptors occurs in both dSPNs and iSPNs. In contrast, iSPNs would exhibit modulation by both A 1- and A 2A-receptors. We demonstrate that A 1-type receptors reduced Ca 2+-currents in all SPNs tested. However, A 2A-type receptors enhanced Ca 2+-currents only in half tested neurons. Intriguingly, to observe the actions of A 2A-type receptors, occupation of A 1-type receptors had to occur first. However, A 1-receptors decreased Ca V2 Ca 2+-currents, while A 2A-type receptors enhanced current through Ca V1 channels. Because these channels have opposing actions on cell discharge, these differences explain in part why iSPNs may be more excitable than dSPNs. It is demonstrated that intrinsic voltage-gated currents expressed in SPNs are effectors of purinergic signaling that therefore play a role in excitability. 相似文献
2.
Receptors for purines and pyrimidines are expressed throughout the cardiovascular system. This study investigated their functional expression in porcine isolated pancreatic arteries. Pancreatic arteries (endothelium intact or denuded) were prepared for isometric tension recording and preconstricted with U46619, a thromboxane A 2 mimetic; adenosine-5′-diphosphate (ADP), uridine-5′-triphosphate (UTP) and MRS2768, a selective P2Y 2 agonist, were applied cumulatively, while adenosine-5′-triphosphate (ATP) and αβ-methylene-ATP (αβ-meATP) response curves were generated from single concentrations per tissue segment. Antagonists/enzyme inhibitors were applied prior to U46619 addition. ATP, αβ-meATP, UTP and MRS2768 induced vasoconstriction, with a potency order of αβ-meATP > MRS2768 > ATP ≥ UTP. Contractions to ATP and αβ-meATP were blocked by NF449, a selective P2X1 receptor antagonist. The contraction induced by ATP, but not UTP, was followed by vasorelaxation. Endothelium removal and DUP 697, a cyclooxygenase-2 inhibitor, had no significant effect on contraction to ATP but attenuated that to UTP, indicating actions at distinct receptors. MRS2578, a selective P2Y 6 receptor antagonist, had no effect on contractions to UTP. ADP induced endothelium-dependent vasorelaxation which was inhibited by MRS2179, a selective P2Y 1 receptor antagonist, or SCH58261, a selective adenosine A 2A receptor antagonist. The contractions to ATP and αβ-meATP were attributed to actions at P2X1 receptors on the vascular smooth muscle, whereas it was shown for the first time that UTP induced an endothelium-dependent vasoconstriction which may involve P2Y 2 and/or P2Y 4 receptors. The relaxation induced by ADP is mediated by P2Y 1 and A 2A adenosine receptors. Porcine pancreatic arteries appear to lack vasorelaxant P2Y 2 and P2Y 4 receptors. 相似文献
3.
We have investigated the presence of thromboxane A 2 (TXA 2) receptor associated with lipid rafts in human platelets and the regulation of platelet function in response to TXA 2 receptor agonists when lipid rafts are disrupted by cholesterol extraction. Platelet aggregation with TXA 2 analogs U46619 and IBOP was almost blunted in cholesterol-depleted platelets, as well as α IIbβ 3 integrin activation and P-selectin exposure. Raft disruption also inhibited TXA 2-induced cytosolic calcium increase and nucleotide release, ruling out an implication of P2Y 12 receptor. An important proportion of TXA 2 receptor (40%) was colocalized at lipid rafts. The presence of the TXA 2 receptor associated with lipid rafts in platelets is important for functional platelet responses to TXA 2. 相似文献
4.
Both 12-hydroxyheptadecatrienoic acid (12-HHT) and thromboxane A 2 (TXA 2) are products derived from prostaglandin H 2 (PGH 2) catalyzed by thromboxane synthase. Whether or not they exhibit similar actions remains to be determined. While TXA 2-induced activation of extracellular signal-regulated kinases (ERKs) has been extensively studied, 12-HHT-induced activation of ERKs has not been explored. We reported for the first time that 12-HHT induced activation of ERKs in human prostate cancer cell line, PC3. We also compared the mechanisms of 12-HHT- and I-BOP-, a TXA 2 mimetic, mediated ERK activation in PC3 cells. The activation of ERKs induced by either agent was shown to involve protein kinase C (PKC)-, protein kinase A (PKA)-, Src kinase and phosphoinositide-3 kinase (PI-3K)-dependent mechanisms in addition to the transactivation of the EGF receptor (EGFR) and the involvement of matrix metalloproteinases (MMPs) based on the sensitivity of the activation to their respective inhibitors. JNK/SAPK and p38 MAPK pathways were responsive to I-BOP but not to 12-HHT stimulation. Both 12-HHT- and I-BOP-induced activations of ERKs were also examined in other human prostate cancer cells, human lung cancer cells, and human lung fibroblast. I-BOP appeared to induce activation of ERKs in most cell lines, whereas 12-HHT induced activation of ERKs only in lung fibroblast in addition to PC3 cells. It appears that TPs are more generally expressed and the potential 12-HHT receptor (s) is expressed in limited specific cell types. Our results suggest that increased expression of thromboxane synthase as seen in prostate tumor may stimulate tumorigenesis as a consequence of concurrent increased synthesis of two fatty acids capable of activating ERKs. 相似文献
5.
The highly potent but modestly selective N-(2-amino-4-methoxy-benzothiazol-7-yl)- N-ethyl-acetamide derivative 2 was selected as the starting point for the design of novel selective A 2B antagonists, due to its excellent potency, and good drug-like properties. A series of compounds containing nonaromatic amides or ureas of five- or six-membered rings, and also bearing an m-trifluoromethyl-phenyl group (shown to impart superior potency) was prepared and evaluated for their selectivity against the A 2A and A 1 receptors. This work resulted in the identification of compound 30, with excellent potency and high selectivity against both A 2A and A 1 receptors. 相似文献
6.
Oxidative stress has been strongly implicated in pathological processes. Isoketals are highly reactive γ-ketoaldehydes of the isoprostanes pathway of free radical-induced peroxidation of arachidonic acid that are analogous to cyclooxygenase-derived levuglandins. Because aldehydes, that are much less reactive than isoketals, have been shown to trigger platelet activation, we investigated the effect of one isoketal (E 2-IsoK) on platelet aggregation. Isoketal potentiated aggregation and the formation of thromboxane B 2 in platelets challenged with collagen at a concentration as low as 1 nM. Moreover, the potentiating effect of 1 nM isoketal on collagen-induced platelet aggregation was prevented by pyridoxamine, an effective scavenger of γ-ketoaldehydes. Furthermore, we provide evidence for the involvement of p38 mitogen-activated protein kinase in isoketal-mediated platelet priming, suggesting that isoketals may act upstream the activation of collagen-induced cytosolic phospholipase A 2. Additionally, the incubation of platelets with 1 nM isoketal led to the phosphorylation of cytosolic phospholipase A 2. The cytosolic phopholipase A 2 inhibitors AACOCF3 and MAFP both fully prevented the increase in isoketal-mediated platelet aggregation challenged with collagen. These results indicate that isoketals could play an important role in platelet hyperfunction observed in pathological states such as atherosclerosis and thrombosis through the activation of the endogenous arachidonic acid cascade. 相似文献
7.
Limonene is a major aromatic compound in essential oils extracted from citrus rind. The application of limonene, especially in aromatherapy, has expanded significantly, but its potential effects on cellular metabolism have been elusive. We found that limonene directly binds to the adenosine A 2A receptor, which may induce sedative effects. Results from an in vitro radioligand binding assay showed that limonene exhibits selective affinity to A 2A receptors. In addition, limonene increased cytosolic cAMP concentration and induced activation of protein kinase A and phosphorylation of cAMP-response element-binding protein in Chinese hamster ovary cells transfected with the human adenosine A 2A receptor gene. Limonene also increased cytosolic calcium concentration, which can be achieved by the activation of adenosine A 2A receptors. These findings suggest that limonene can act as a ligand and an agonist for adenosine A 2A receptors. 相似文献
8.
Sixteen known 5-HT 3 receptor blockers, including clozapine, fully or partially reverse the inhibitory effect of 1 M GABA on [ 35S]TBPS binding, indicating that they are also GABA A antagonists, some of them selective for subsets of GABA A receptors. The 5-HT 3 receptor blocker, ondansetron, has been reported to produce some antipsychotic and anxiolytic effects. However, no antipsychotic effects have been reported for a large number of highly potent 5-HT 3 receptor blockers. Like clozapine, ondansetron partially reverses the inhibitory effect of GABA on [ 35S]TBPS binding. Additivity experiments suggest that ten 5-HT 3 receptor blockers tested at low concentrations preferentially block subtypes of GABA A receptors that are among those blocked by clozapine. Wiley and Porter (29) reported that MDL-72222, the most potent GABA A antagonist decribed here, partially generalizes (71%) with clozapine in rats trained to discriminate an interoceptive clozapine stimulus, but only at a dose that severly decreases responding. Tropisetron (ICS-205,930) exhibits both GABA-positive and GABA-negative effects. R-(+)-zacopride is 6-fold more potent than S-(–)-zacopride as a GABA A antagonist. We conclude that the observed antipsychotic and, possibly, anxiolytic effects of some 5-HT 3 receptor blockers are due to selective antagonism of certain GABA A receptors, and not to blockade of 5-HT 3 receptors. We speculate that the anxiolytic and sedative effects of clozapine and several other antipsychotic drugs may be due to selective blockade of 122 GABA A receptors which are preferentially located on certain types of GABAergic interneurons (probably parvalbumin positive). Blockade of these receptors will increase the inhibitory output of these interneurons. So far, no highly potent GABA A antagonists with clozapine-like selectivity have been identified. Such compounds may exhibit improved clozapine-like antipsychotic activity. 相似文献
9.
6-Hydroxydopamine (6-OHDA) is the most used toxin in experimental Parkinson’s disease (PD) models. 6-OHDA shows high affinity for the dopamine transporter and once inside the neuron, it accumulates and undergoes non-enzymatic auto-oxidation, promoting reactive oxygen species (ROS) formation and selective damage of catecholaminergic neurons. In this way, our group has established a 6-OHDA in vitro protocol with rat striatal slices as a rapid and effective model for screening of new drugs with protective effects against PD. We have shown that co-incubation with guanosine (GUO, 100 μM) prevented the 6-OHDA-induced damage in striatal slices. As the exact GUO mechanism of action remains unknown, the aim of this study was to investigate if adenosine A1 (A1R) and/or A2A receptors (A2AR) are involved on GUO protective effects on striatal slices. Pre-incubation with DPCPX, an A1R antagonist prevented guanosine effects on 6-OHDA-induced ROS formation and mitochondrial membrane potential depolarization, while CCPA, an A1R agonist, did not alter GUO effects. Regarding A2AR, the antagonist SCH58261 had similar protective effect as GUO in ROS formation and mitochondrial membrane potential. Additionally, SCH58261 did not affect GUO protective effects. The A2AR agonist CGS21680, although, completely blocked GUO effects. Finally, the A1R antagonist DPCPX, and the A2AR agonist CGS21680 also abolished the preventive guanosine effect on 6-OHDA-induced ATP levels decrease. These results reinforce previous evidence for a putative interaction of GUO with A1R-A2AR heteromer as its molecular target and clearly indicate a dependence on adenosine receptors modulation to GUO protective effect. 相似文献
10.
Vascular endothelial cells respond to biomechanical forces, such as cyclic stretch and shear stress, by altering gene expression. Since endothelial-derived prostanoids, such as prostacyclin and thromboxane A 2, are key mediators of endothelial function, we investigated the effects of cyclic stretch on the expression of genes in human umbilical vein endothelial cells controlling prostanoid synthesis: cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), prostacyclin synthase (PGIS) and thromboxane A 2 synthase (TXAS). COX-2 and TXAS mRNAs were upregulated by cyclic stretch for 24 h. In contrast, PGIS mRNA was decreased and stretch had no effect on COX-1 mRNA expression. We further show that stretch-induced upregulation of COX-2 is mediated by activation of the NF-κβ signaling pathway. 相似文献
11.
1. Serotonin is an intrinsically fluorescent biogenic amine that acts as a neurotransmitter and is found in a wide variety of sites in the central and peripheral nervous system. Serotonergic signaling appears to play a key role in the generation and modulation of various cognitive and behavioral functions.2. Serotonin exerts its diverse actions by binding to distinct cell surface receptors which have been classified into many groups. The serotonin 1A (5-HT 1A) receptor is the most extensively studied of the serotonin receptors and belongs to the large family of seven transmembrane domain G-protein coupled receptors.3. The tissue and sub-cellular distribution, structural characteristics, signaling of the serotonin 1A receptor and its interaction with G-proteins are discussed.4. The pharmacology of serotonin 1A receptors is reviewed in terms of binding of agonists and antagonists and sensitivity of their binding to guanine nucleotides.5. Membrane biology of 5-HT 1A receptors is presented using the bovine hippocampal serotonin 1A receptor as a model system. The ligand binding activity and G-protein coupling of the receptor is modulated by membrane cholesterol thereby indicating the requirement of cholesterol in maintaining the receptor organization and function. This, along with the reported detergent resistance characteristics of the receptor, raises important questions on the role of membrane lipids and domains in the function of this receptor. 相似文献
12.
We investigated the role of a 1 Hz low-strength magnetic pulse superimposed on the environmental electromagnetic field (emf) on the secretion of anti-aggregant (prostacyclin or PGI 2) and pro-aggregant (thromboxane A 2 or TXA 2) agents in the EaHy-926 endothelial cell line. We established that magnetic pulse exposure has opposite effects on the two secretions: PGI 2 is decreased, whereas TXA 2 is increased, with a PGI 2/TXA 2 ratio shifted toward thrombosis. We also show that the effect of the magnetic field depends on its orientation, normal or parallel, to the cell monolayer. Finally, we show that the amplitude of the effect does not increase with the magnitude of the magnetic pulse, particularly with PGI 2 secretion, which is increased as the field magnitude is decreased, suggesting a new concept for defining a threshold for health hazards. 相似文献
13.
Adenosine is an important regulatory metabolite and an inhibitor of platelet activation. Adenosine released from different
cells or generated through the activity of cell-surface ectoenzymes exerts its effects through the binding of four different
G-protein-coupled adenosine receptors. In platelets, binding of A 2 subtypes (A 2A or A 2B) leads to consequent elevation of intracellular cyclic adenosine monophosphate, an inhibitor of platelet activation. The
significance of this ligand and its receptors for platelet activation is addressed in this review, including how adenosine
metabolism and its A 2 subtype receptors impact the expression and activity of adenosine diphosphate receptors. The expression of A 2 adenosine receptors is induced by conditions such as oxidative stress, a hallmark of aging. The effect of adenosine receptors
on platelet activation during aging is also discussed, as well as potential therapeutic applications. 相似文献
14.
experiments indicate that thromboxane A 2 (TA 2) is a potent platelet aggregator and vascular constrictor. However, it is unclear what roles these specific actions may contribute in the pathophysiology of myocardial ischemia. Carbocyclic thromboxane A 2 (CTA 2), a TA 2 analog, constricts isolated perfused cat coronary arteries, but does not aggregate platelets, and thus appeared useful to clarify these separate actions of TA 2. In anesthetized cats, radioactive labeled microspheres were injected into the left atrium for measurement of cardiac output and tissue blood flows. Compared to control measurements, CTA 2 infusion (4.8 μg·kg ?1·min ?1 to 10 min) significantly decreased cardiac output from 347 ± 16 ml·min ?1 to 248 ± 16 ml·min ?1 (p<0.025). Furthermore, V7 CTA 2 also significantly reduced blood flow to the left ventricle by 33 ± 7%, but did not alter heart rate or MABP in the intact cat. In cats subjected to left anterior descending coronary artery occlusion, infusion of CTA 2 (1 μg·min ?1 for 120 minutes) 30 min after ligation resulted in a significantly reduced myocardial cellular integrity as measured by myocardial creatine kinase activity (p<0.01) or percent bound myocardial cathepsin D (p<0.01). Thus, these data suggest that activation of vascular thromboxane receptors as well as direct cellular damage may play a role in the pathophysiology of myocardial ischemia. 相似文献
15.
Caffeine, a stimulant largely consumed around the world, is a non-selective adenosine receptor antagonist, and therefore caffeine actions at synapses usually, but not always, mirror those of adenosine. Importantly, different adenosine receptors with opposing regulatory actions co-exist at synapses. Through both inhibitory and excitatory high-affinity receptors (A1R and A2R, respectively), adenosine affects NMDA receptor (NMDAR) function at the hippocampus, but surprisingly, there is a lack of knowledge on the effects of caffeine upon this ionotropic glutamatergic receptor deeply involved in both positive (plasticity) and negative (excitotoxicity) synaptic actions. We thus aimed to elucidate the effects of caffeine upon NMDAR-mediated excitatory post-synaptic currents (NMDAR-EPSCs), and its implications upon neuronal Ca2+ homeostasis. We found that caffeine (30–200 μM) facilitates NMDAR-EPSCs on pyramidal CA1 neurons from Balbc/ByJ male mice, an action mimicked, as well as occluded, by 1,3-dipropyl-cyclopentylxantine (DPCPX, 50 nM), thus likely mediated by blockade of inhibitory A1Rs. This action of caffeine cannot be attributed to a pre-synaptic facilitation of transmission because caffeine even increased paired-pulse facilitation of NMDA-EPSCs, indicative of an inhibition of neurotransmitter release. Adenosine A2ARs are involved in this likely pre-synaptic action since the effect of caffeine was mimicked by the A2AR antagonist, SCH58261 (50 nM). Furthermore, caffeine increased the frequency of Ca2+ transients in neuronal cell culture, an action mimicked by the A1R antagonist, DPCPX, and prevented by NMDAR blockade with AP5 (50 μM). Altogether, these results show for the first time an influence of caffeine on NMDA receptor activity at the hippocampus, with impact in neuronal Ca2+ homeostasis. 相似文献
16.
Two selective thromboxane A 2 synthetase inhibitors, imidazole and 9,11-azoprosta-5,13-dienoic acid (azo analog I) were compared to determine their effects on the quantitative formation of thromboxane B 2 and prostaglandin E 2 accompanying human platelet aggregation. Azo analog I was at least 200 times more potent, on a molar basis, than imidazole in suppressing thromboxane B 2 formation in either platelet-rich plasma or washed platelet suspensions aggregated with arachidonic acid or prostaglandin H 2. The inhibitors differed in their effect on the aggregation response itself. Azo analog I selectively suppressed thromboxane A 2 formation with an accompanying, parallel, suppression of the platelet aggregation.Imidazole selectively suppressed thromboxane A 2 formation, but only suppressed the accompanying aggregation in platelet rich plasma, and not washed platelet suspensions. The results indicate that azo analog I functions by competitive inhibition of prostaglandin H 2 on the thromboxane synthetase, and that imidazole, while it suppresses thromboxane A 2 formation, may have an associated agonist activity that enhances platelet aggregation. The data presented support this hypothesis, and they emphasize the importance of thromboxane A 2 in arachidonate mediated platelet aggregation. 相似文献
17.
The incorporation of extra binding groups onto known ligands is a powerful tool for the development of more potent and selective
agents at target sites such as the GABA receptors. In the present work we have attempted to build on the activity of the know
potent GABA A agonist 4-ACP-3-CA and its cis and trans saturated analogues CACP and TACP. We have investigated reactions to add thiol substituents to the α,β-unsaturated system
of 4-ACP-3-CA. The reaction was successful with a limited number of thiols but gave products of mixed stereochemistry. The
resultant thioether amino acids were screened for activity at human recombinant α 1β 2 γ 2L GABA A receptors. The most interesting derivative was the benzylthioether which acted as an antagonist with an IC 50 of 42 μM for the inhibition of a GABA EC 50 dose (50 μM). This study has shown that GABA analogues derived by thiol addition to 4-aminocyclopent-1-enecarboxylic acid display interesting antagonist activity at the α 1β 2γ 2L GABA A receptor.
Special issue article in honour of Dr. Graham Johnston. 相似文献
18.
Serotonergic neurotransmission in prefrontal cortex (PFC) plays a key role in regulating emotion and cognition under normal
and pathological conditios. Increasing evidence suggests that serotonin receptors are involved in the complex regulation of
GABAergic inhibitory transmission in PFC. Activation of postsynaptic 5-HT 2 receptors in PFC pyramidal neurons inhibits GABA A-receptor currents via phosphorylation of GABA A receptor γ2 subunits by RACK1-anchored PKC. In contrast, activation of postsynaptic 5-HT 4 receptors produces an activity-dependent bi-directional regulation of GABA-evoked currents in PFC pyramidal neurons, which
is mediated through phosphorylation of GABA A-receptor β subunits by anchored PKA. On the presynaptic side, GABAergic inhibition is regulated by 5-HT through the activation
of 5-HT 2, 5-HT 1, and 5-HT 3 receptors on GABAergic intereneurons. These data provide a molecular and cellular mechanism for serotonin to dynamically
regulate synaptic transmission and neuronal excitability in the PFC network, which may underlie the actions of many antidepressant
and antipsychotic drugs. 相似文献
19.
The peroxiredoxins (Prxs) constitute a very large and highly conserved family of thiol-based peroxidases that has been discovered only very recently. We consider here these enzymes through the angle of their discovery, and of some features of their molecular and physiological functions, focusing on complex phenotypes of the gene mutations of the 2-Cys Prxs subtype in yeast. As scavengers of the low levels of H 2O 2 and as H 2O 2 receptors and transducers, 2-Cys Prxs have been highly instrumental to understand the biological impact of H 2O 2, and in particular its signaling function. 2-Cys Prxs can also become potent chaperone holdases, and unveiling the in vivo relevance of this function, which is still not established, should further increase our knowledge of the biological impact and toxicity of H 2O 2. The diverse molecular functions of 2-Cys Prx explain the often-hard task of relating them to peroxiredoxin genes phenotypes, which underscores the pleiotropic physiological role of these enzymes and complex biologic impact of H 2O 2. 相似文献
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