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1.
Modulation of NMDA receptors by glycine — introduction to some basic aspects and recent developments
Dr. C. G. Parsons W. Danysz M. Hesselink S. Hartmann B. Lorenz C. Wollenburg G. Quack 《Amino acids》1998,14(1-3):207-216
Summary Glycine is a co-agonist at NMDA receptors and it's presence is a prerequisite for channel activation by glutamate or NMDA. Physiological concentrations reduce one form of NMDA receptor-desensitization. Interactions between the glycineB site and other domains of the NMDA receptor are complex and include the glutamate, Mg+ and polyamines sites. Glycine shows different affinities at various NMDA receptor subtypes probably via to allosteric interactions between NMDA2 subunits and the glycine recognition site on the NMDAR1 subunit. There is still some debate whether the glycineB site is saturatedin vivo but it seems likely that this depends on regional differences in receptor subtype expression, local glycine or D-serene concentrations and the expression of specific glycine transporters.GlycineB antagonists and partial agonists have been reported to have good therapeutic indices as neuroprotective agents against focal ischaemia and trauma, anti-epileptics, anxiolytics, anti-psychotomimetics and in models of chronic pain. They clearly lack two potentially serious side effects classically associated with NMDA receptor blockade, namely neurodegenerative changes in the cingulate/retrosplenial cortex and psychotomimetic-like effects. This improved therapeutic profile may be partially due to the ability of full glycineB antagonists to reveal Gycne-sensitive desensitization and possibly also via functional and/or regional NMDA receptor subtype selectivity. 相似文献
2.
Summary We have shown that members of a new series of tricyclic pyridophthalazine diones, defined as glycineB site NMDA antagonistsin vitro, are selective and systemically active NMDA antagonistsin vivo. In electrophysiological tests in -chloralose anaesthetised rats, these compounds reduced nociceptive reflex responses. In conscious rats they displayed analgesic properties. These glycineB antagonists were compared electrophysiologically with several uncompetitive NMDA channel blockers. The degree of voltage dependence previously reportedin vitro related to the effectiveness of the agents against different amplitude nociceptive responses of spinal cord neuronesin vivo. 相似文献
3.
Summary. There is general agreement that moderate affinity uncompetitive NMDA receptor antagonists combine good efficacy and tolerability
in animal models of disturbances in glutamatergic transmission. There are several theories on which properties are important
for this profile including 1, rapid access to the channel at the start of pathological overactivity 2, rapid, voltage-dependent
relief of blockade during physiological synaptic activation and 3, partial untrapping. Merz has developed a series of novel
uncompetitive NMDA receptor antagonists based on the cyclohexane structure. In cultured hippocampal neurones MRZ 2/579 (1-amino-1,3,3,5,5-pentamethyl-cyclohexane)
shows similar blocking kinetics to memantine (Kon 10.7 * 104 M−1 sec−1, Koff 0.20 sec−1 at −70 mV) and binds at the same depth in the NMDA receptor channel (δ = 0.8). The potency of MRZ 2/579 assessed as Kd = Koff/Kon = 1.87 μM agrees well with the IC50 of 1.29 μM against steady-state currents in cultured hippocampal neurones (at −70 mV) and with the Ki in [3H]-MK-801 binding of 0.65 μM. MRZ 2/579 protected cultured cortical neurones against glutamate toxicity with an IC50 of 2.16 μM and was also effective in protecting hippocampal slices against hypoxia / hypoglycaemia-induced reduction of fEPSP amplitude
in CA1 with an EC50 of 7.01 μM. MRZ 2/579 has similar potency and bio-availability to memantine in vivo assessed using microdialysis, microiontophoresis and MES-induced seizures. Initial characterization in animal models provides
strong support for the assump-tion that MRZ 2/579 could be a useful therapeutic in morphine/alcohol dependence, inhibition
of morphine tolerance, chronic pain and as a neuroprotective agent.
Received August 31, 1999 Accepted September 20, 1999 相似文献
4.
Hong-Yi Zhou Shao-Rui Chen Hee-Sun Byun Hong Chen Li Li Hee-Dong Han Gabriel Lopez-Berestein Anil K. Sood Hui-Lin Pan 《The Journal of biological chemistry》2012,287(40):33853-33864
Loss of synaptic inhibition by γ-aminobutyric acid and glycine due to potassium chloride cotransporter-2 (KCC2) down-regulation in the spinal cord is a critical mechanism of synaptic plasticity in neuropathic pain. Here we present novel evidence that peripheral nerve injury diminishes glycine-mediated inhibition and induces a depolarizing shift in the reversal potential of glycine-mediated currents (Eglycine) in spinal dorsal horn neurons. Blocking glutamate N-methyl-d-aspartate (NMDA) receptors normalizes synaptic inhibition, Eglycine, and KCC2 by nerve injury. Strikingly, nerve injury increases calcium-dependent calpain activity in the spinal cord that in turn causes KCC2 cleavage at the C terminus. Inhibiting calpain blocks KCC2 cleavage induced by nerve injury and NMDA, thereby normalizing Eglycine. Furthermore, calpain inhibition or silencing of μ-calpain at the spinal level reduces neuropathic pain. Thus, nerve injury promotes proteolytic cleavage of KCC2 through NMDA receptor-calpain activation, resulting in disruption of chloride homeostasis and diminished synaptic inhibition in the spinal cord. Targeting calpain may represent a new strategy for restoring KCC2 levels and tonic synaptic inhibition and for treating chronic neuropathic pain. 相似文献
5.
Yinfeng Yang Weiwei Zhou Yaorong Chen Qian Wu 《Journal of biomolecular structure & dynamics》2019,37(13):3467-3481
Adenosine is a ubiquitous endogenous nucleoside that controls numerous physiological functions via interacting with its specific G-coupled receptors. Activation of adenosine receptors (AdoRs), particularly A2B AdoRs promotes the release of inflammatory cytokines; reduces vascular permeabilization and induces angiogenesis, thereby making A2B AdoR becomes a potentially pharmacological target for drug development. Presently, for investigating the structural determinants of 164 xanthine derivatives as A2B AdoR antagonists, we performed an in silico study integrating with 3D-QSAR, docking and molecular dynamics (MD) simulation. The obtained optimal model shows strong predictability (Q2?=?0.647, R2ncv?=?0.955, and R2pred?=?0.848). Additionally, to explore the binding mode of the ligand with A2B AdoR and to understand their binding mechanism, docking analysis, MD simulations (20?ns), and the calculation of binding free energy were also carried out. Finally, the structural determinants of these xanthine derivatives were identified and a total of 20 novel A2B AdoR antagonists with improved potency were computationally designed, and their synthetic feasibility and selectivity were also evaluated. The information derived from the present study offers a better appreciation for exploring the interaction mechanism of the ligand with A2B AdoR, which could be helpful for designing novel potent A2B AdoR antagonists.
Communicated by Ramaswamy H. Sarma 相似文献
6.
Chi Ting Leung Ang Li Juni Banerjee Zhan-Guo Gao Taku Kambayashi Kenneth A. Jacobson Mortimer M. Civan 《Purinergic signalling》2014,10(3):465-475
Mast cell degranulation triggers hypersensitivity reactions at the body–environment interface. Adenosine modulates degranulation, but enhancement and inhibition have both been reported. Which of four adenosine receptors (ARs) mediate modulation, and how, remains uncertain. Also uncertain is whether adenosine reaches mast cell ARs by autocrine ATP release and ecto-enzymatic conversion. Uncertainties partly reflect species and cell heterogeneity, circumvented here by focusing on homogeneous human LAD2 cells. Quantitative PCR detected expression of A2A, A2B, and A3, but not A1, ARs. Nonselective activation of ARs with increasing NECA monotonically enhanced immunologically or C3a-stimulated degranulation. NECA alone stimulated degranulation slightly. Selective AR antagonists did not affect C3a-stimulated degranulation. NECA''s enhancement of C3a-triggered degranulation was partially inhibited by separate application of each selective antagonist, and abolished by simultaneous addition of antagonists to the three ARs. Only the A2A antagonist separately inhibited NECA''s enhancement of immunologically stimulated degranulation, which was abolished by simultaneous addition of the three selective antagonists. Immunological or C3a activation did not stimulate ATP release. NECA also enhanced immunologically triggered degranulation of mouse bone marrow derived mast cells (BMMCs), which was partially reduced only by simultaneous addition of the three antagonists or by the nonselective antagonist . BMMCs also expressed A2A, A2B, and A3 ARs. but not A1AR detectably. We conclude that (a) A1AR is unnecessary for LAD2 degranulation or AR enhancement; (b) A2A, A2B, and A3 ARs all contribute to pharmacologic AR enhancement of LAD2 and BMMC degranulation; and (c) LAD2 cells depend on microenvironmental adenosine to trigger AR modulation. CGS15943相似文献
7.
The present study describes the effects of gamma-aminobutyric acid (GABA) and its antagonists, bicuculline and 2-hydroxysaclofen,
on visual responses of neurons in the pigeon nucleus lentiformis mesencephali (nLM). The results indicate that GABA significantly
reduces both spontaneous activity and visual responsiveness, and GABAA antagonist bicuculline but not GABAB antagonist 2-hydroxysaclofen enhances visual responses of nLM cells examined. Furthermore, inhibition produced by motion
in the null-direction of pretectal neurons is diminished by bicuculline but not by 2-hydroxysaclofen. It is therefore concluded
that the null-direction inhibition of directional cells in the pigeon nLM is predominantly mediated by GABA and GABAA receptors. This inhibition may at least in part underlie directional asymmetry of optokinetic responses. 相似文献
8.
Nicotine or cocaine, when administered intravenously, induces an increase of extracellular dopamine in the nucleus accumbens. The nicotine-mediated increase was shown to occur at least in part through increase of the activity of dopamine neurons in the ventral tegmental area. As part of our continuing studies of the mechanisms of nicotine effects in the brain, in particular, effects on reward and cognitive mechanisms, in the present study we examined the role of various receptors in the ventral tegmental area in nicotine and cocaine reward. We assayed inhibition of the increase of dopamine in the nucleus accumbens induced by intravenous nicotine or cocaine administration by antagonists administered into the ventral tegmental area. Nicotine-induced increase of accumbal dopamine release was inhibited by intrategmental nicotinic (mecamylamine), muscarinic (atropine), dopaminergic (D1: SCH 23390, D2: eticlopride), and NMDA glutamatergic (MK 801) and GABAB (saclofen) antagonists, but not by AMPA-kainate (CNQX, GYKI-52466) antagonists under our experimental circumstances. The intravenous cocaine-induced increase of dopamine in the nucleus accumbens was inhibited by muscarinic (atropine), dopamine 2 (eticlopride), and GABAB (saclofen) antagonists but not by antagonists to nicotinic (mecamylamine), dopamine D1 (SCH 23390), glutamate (MK 801), or AMPA-kainate (CNQX, GYKI-52466) receptors. Antagonists administered in the ventral tegmental area in the present study had somewhat different effects when they were previously administered intravenously. When administered intravenously atropine did not inhibit cocaine effects. The inhibition by atropine may be indirect, since this compound, when administered intrategmentally, decreased basal dopamine levels in the accumbens. The findings indicate that a number of receptors in the ventral tegmental area mediate nicotine-induced dopamine changes in the nucleus accumbens, a major component of the nicotine reward mechanism. Some, but not all, of these receptors in the ventral tegmental area also seem to participate in the reward mechanism of cocaine. The importance of local receptors in the ventral tegmental area was further indicated by the increase in accumbal dopamine levels after intrategmental administration of nicotine or also cocaine. 相似文献
9.
Steven M. Bromidge Steven Dabbs David T. Davies Susannah Davies D. Malcolm Duckworth Ian T. Forbes Angela Gadre Peter Ham Graham E. Jones Frank D. King Damian V. Saunders Kevin M. Thewlis Deepa Vyas Thomas P. Blackburn Vicky Holland Guy A. Kennett Graham J. Riley Martyn D. Wood 《Bioorganic & medicinal chemistry》1999,7(12):5086
A model series of 5-HT2C antagonists have been prepared by rapid parallel synthesis. These N-substituted phenyl-N′-pyridin-3-yl ureas were found to have a range of 5-HT2C receptor affinities and selectivities over the closely related 5-HT2A receptor. Extrapolation of simple SAR, derived from this set of compounds, to the more active but synthetically more complex 1-(3-pyridyl-carbamoyl)indoline series allowed us to target optimal substitution patterns and identify potent and selective 5-HT2C/2B antagonists. 相似文献
10.
Zhi Li Lijuan Kou Xinzhen Fu Zeping Xie Maolei Xu Lin Guo Tiantian Lin Shizhou Gong Shumin Zhang Ming Liu 《Journal of enzyme inhibition and medicinal chemistry》2022,37(1):1514
A series of novel dual A2A/A2B AR antagonists based on the triazole-pyrimidine-methylbenzonitrile core were designed and synthesised. The A2A AR antagonist cAMP functional assay results were encouraging for most target compounds containing quinoline or its open-ring bioisosteres. In addition, compound 7i displayed better inhibitory activity on A2B AR (IC50 14.12 nM) and higher potency in IL-2 production than AB928. Moreover, molecular docking studies were carried out to explain the rationality of molecular design and the activity of compound 7i. Further studies on 7f and 7i revealed good liver microsomes stabilities and acceptable in vivo PK profiles. This study provides insight into the future development of dual A2A/A2B AR antagonists for cancer immunotherapy. 相似文献
11.
Novel approaches to targeting glutamate receptors for the treatment of chronic pain: review article 总被引:2,自引:0,他引:2
Chizh BA 《Amino acids》2002,23(1-3):169-176
Summary. Glutamatergic mechanisms are implicated in acute and chronic pain, and there is a great diversity of glutamate receptors
that can be used as targets for novel analgesics. Some approaches, e.g. NMDA receptor antagonism, have been validated clinically,
however, the central side-effects have remained the main problem with most compounds. Recently, some novel approaches have
been explored as new compounds targeting some modulatory sites at the NMDA receptor (glycineB and NR2B-subtype selective antagonists), as well as kainate and metabotropic glutamate receptors, have been discovered. Many
of these compounds have demonstrated efficacy in animal models of chronic pain, and some of them appear to have a reduced
side-effect liability compared to clinically tested NMDA antagonists. These recent advances are reviewed in the present work.
Received July 6, 2001 Accepted August 6, 2001 Published online June 26, 2002 相似文献
12.
Anne Baudry Juliette Bitard Sophie Mouillet-Richard Morgane Locker Anne Poliard Jean-Marie Launay Odile Kellermann 《The Journal of biological chemistry》2010,285(34):26066-26073
In previous studies, we observed that mice knocked out for the serotonin-2B receptor (5-HT2BR) show defects in bone homeostasis. The present work focuses on the downstream targets relaying the anabolic function of this receptor in osteoblasts. A functional link between the 5-HT2BR and the activity of the tissue-nonspecific alkaline phosphatase (TNAP) is established using the C1 osteoprogenitor cell line. During C1 osteogenic differentiation, both 5-HT2BR and TNAP mRNA translations are delayed with respect to extracellular matrix deposition. Once the receptor is expressed, it constitutively controls TNAP activity at a post-translational level along the overall period of mineral deposition. Indeed, pharmacological inhibition of the 5-HT2BR intrinsic activity or shRNA-mediated 5-HT2BR knockdown prevents TNAP activation, but not its mRNA translation. In contrast, agonist stimulation of the receptor further increases TNAP activity during the initial mineralization phase. Building upon our previous observations that the 5-HT2BR couples with the phospholipase A2 pathway and prostaglandin production at the beginning of mineral deposition, we show that the 5-HT2BR controls leukotriene synthesis via phospholipase A2 at the terminal stages of C1 differentiation. These two 5-HT2BR-dependent eicosanoid productions delineate distinct time windows of TNAP regulation during the osteogenic program. Finally, prostaglandins or leukotrienes are shown to relay the post-translational activation of TNAP via stimulation of the phosphatidylinositol-specific phospholipase C. In agreement with the above findings, primary calvarial osteoblasts from 5-HT2BR-null mice exhibit defects in TNAP activity. 相似文献
13.
Anke C. Schiedel Svenja K. Lacher Carsten Linnemann Percy A. Knolle Christa E. Müller 《Purinergic signalling》2013,9(3):351-365
The effects of standard adenosine receptor (AR) agonists and antagonists on the proliferation of human T lymphocytes, unstimulated and phytohemagglutinin-stimulated human peripheral blood lymphocytes (PBL), and Jurkat T cells were investigated. Real-time PCR measurements confirmed the presence of all four AR subtypes on the investigated cells, although at different expression levels. A2A ARs were predominantly expressed in PBL and further upregulated upon stimulation, while malignant Jurkat T cells showed high expression levels of A1, A2A, and A2B ARs. Cell proliferation was measured by [3H]-thymidine incorporation assays. Several ligands, including the subtype-selective agonists CPA (A1), BAY60-6583 (A2B), and IB-MECA (A3), and the antagonists PSB-36 (A1), MSX-2 (A2A), and PSB-10 (A3) significantly inhibited cell proliferation at micromolar concentrations, which were about three orders of magnitude higher than their AR affinities. In contrast, further investigated AR ligands, including the agonists NECA (nonselective) and CGS21680 (A2A), and the antagonists preladenant (SCH-420814, A2A), PSB-1115 (A2B), and PSB-603 (A2B) showed no or only minor effects on lymphocyte proliferation. The anti-proliferative effects of the AR agonists could not be blocked by the corresponding antagonists. The non-selective AR antagonist caffeine stimulated phytohemagglutinin-activated PBL with an EC50 value of 104 μM. This is the first study to compare a complete set of commonly used AR ligands for all subtypes on lymphocyte proliferation. Our results strongly suggest that these compounds induce an inhibition of lymphocyte proliferation and cell death through AR-independent mechanisms. 相似文献
14.
Knockout (KO) mice that lack the dopamine transporter (SL6A3; DAT) display increased locomotion that can be attenuated, under some circumstances, by administration of drugs that normally produce psychostimulant-like effects, such as amphetamine and methylphenidate. These results have led to suggestions that DAT KO mice may model features of attention deficit hyperactivity disorder (ADHD) and that these drugs may act upon serotonin (5-HT) systems to produce these unusual locomotor decreasing effects. Evidence from patterns of brain expression and initial pharmacologic studies led us to use genetic and pharmacologic approaches to examine the influence of altered 5-HT1B receptor activity on hyperactivity in DAT KO mice. Heterozygous 5-HT1B KO and pharmacologic 5-HT1B antagonism both attenuated locomotor hyperactivity in DAT KO mice. Furthermore, DAT KO mice with reduced, but not eliminated, 5-HT1B receptor expression regained cocaine-stimulated locomotion, which was absent in DAT KO mice with normal levels of 5-HT1B receptor expression. Further experiments demonstrated that the degree of habituation to the testing apparatus determined whether cocaine had no effect on locomotion in DAT KO or reduced locomotion, helping to resolve differences among prior reports. These findings of complementation of the locomotor effects of DAT KO by reducing 5-HT1B receptor activity underscore roles for interactions between specific 5-HT receptors and dopamine (DA) systems in basal and cocaine-stimulated locomotion and support evaluation of 5-HT1B antagonists as potential, non-stimulant ADHD therapeutics. 相似文献
15.
J.D. Líbano-Soares 《生物化学与生物物理学报:生物膜》2008,1778(5):1316-1323
In a previous paper we showed that bradykinin (BK), interacting with its B2 receptor, inhibits proximal tubule Na+-ATPase activity but does not change (Na+ + K+)ATPase activity. The aim of this paper was to investigate the molecular mechanisms involved in B2-mediated modulation of proximal tubule Na+-ATPase by BK. To abolish B1 receptor-mediated effects, all experiments were carried out in the presence of (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Leu), des-Arg9-[Leu8]-BK (DALBK), a specific antagonist of B1 receptor. A dual effect on the Na+-ATPase activity through the B2 receptor was found: short incubation times (1-10 min) stimulate the enzyme activity; long incubation times (10-60 min) inhibit it. The stimulatory effect of BK is mediated by activation of phosphoinositide-specific phospholipase C β (PI-PLCβ)/protein kinase C (PKC); its inhibitory action is mediated by Ca2+-independent phospholipase A2 (iPLA2). Prior activation of the PI-PLCβ/PKC pathway is required to activate the iPLA2-mediated inhibitory phase. These results reveal a new mechanism by which BK can modulate renal sodium excretion: coupling between B2 receptor and activation of membrane-associated iPLA2. 相似文献
16.
Gessi S Varani K Merighi S Leung E Mac Lennan S Baraldi PG Borea PA 《Purinergic signalling》2006,2(4):583-588
The adenosine A2B receptor is the least well characterized of the four adenosine subtypes due to the lack of potent and selective agonists and antagonists. Despite the widespread distribution of A2B receptor mRNA, little information is available with regard to their function. The characterization of A2B receptors, through radioligand binding studies, has been performed, until now, by using low-affinity and non-selective antagonists like 1,3-dipropyl-8-cyclopentylxanthine ([3H]DPCPX),(4-(2-[7-amino-2-(2-furyl)-[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-ylamino]ethyl)-phenol ([3H]ZM 241385) and 3-(3,4-aminobenzyl)-8-(4-oxyacetate)phenyl-1-propyl-xanthine ([125I]ABOPX). Recently, high-affinity radioligands for A2B receptors, [N-(4-cyanophenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)-phenoxy]acetamide ([3H]MRS 1754), N-(2-(2-Phenyl-6-[4-(2,2,3,3-tetratritrio-3-phenylpropyl)-piperazine-1-carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl)-acetamide ([3H]OSIP339391) and N-benzo[1,3]dioxol-5-yl-2-[5-(1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yloxy]-acetamide] ([3H]MRE 2029F20), have been introduced. This minireview offers an overview of these recently developed radioligands and the most important applications of drugs towards A2B receptors. 相似文献
17.
Summary. Some synthetic taurine analogues, namely ethanolamine-O-sulphate (EOS), N,N-dimethyltaurine (DMT), N,N,N-trimethyltaurine (TMT) and 2-aminoethylphosphonic acid (AEP) were shown to interact with rabbit brain GABAA- or GABAB-receptors, while (±)piperidine-3-sulfonic acid (PSA) inhibited the activity of rabbit brain 4-aminobutyrate transaminase.
This suggests that they behave like direct/indirect GABA agonists or GABA antagonists and affect thermoregulation and gross
motor behaviour (GMB) which are under GABA control. In the present study micromole (1.2–48) amounts of these compounds were
i.c.v. injected in conscious, restrained rabbits while monitoring rectal temperature (RT), ear skin temperature (EST) and
GMB. AEP, EOS, DMT and TMT induced a dose-related hyperthermia, ear vasoconstriction and excitation of GMB, while PSA induced
a dose-related hypothermia, ear vasodilation and inhibition of GMB. EOS antagonized in a dose-related fashion hypothermia
induced by 60 nmol THIP, a GABAA agonist, while AEP, DMT and TMT counteracted that induced by 8 nmol R(-)Baclofen, a GABAB agonist.
In conclusion, EOS and AEP, DMT, TMT seem to act as GABAA and GABAB antagonists, respectively, while PSA behaves like an indirect GABA agonist, all affecting the central mechanisms which drive
rabbit thermoregulation. 相似文献
18.
Serotonin modulates agonistic and reproductive behavior across vertebrate species. 5HT1A and 5HT1B receptors mediate many serotonergic effects on social behavior, but other receptors, including 5HT2 receptors, may also contribute. We investigated serotonergic regulation of electrocommunication signals in the weakly electric fish Apteronotus leptorhynchus. During social interactions, these fish modulate their electric organ discharges (EODs) to produce signals known as chirps. Males chirp more than females and produce two chirp types. Males produce high-frequency chirps as courtship signals; whereas both sexes produce low-frequency chirps during same-sex interactions. Serotonergic innervation of the prepacemaker nucleus, which controls chirping, is more robust in females than males. Serotonin inhibits chirping and may contribute to sexual dimorphism and individual variation in chirping. We elicited chirps with EOD playbacks and pharmacologically manipulated serotonin receptors to determine which receptors regulated chirping. We also asked whether serotonin receptor activation generally modulated chirping or more specifically targeted particular chirp types. Agonists and antagonists of 5HT1B/1D receptors (CP-94253 and GR-125743) did not affect chirping. The 5HT1A receptor agonist 8OH-DPAT specifically increased production of high-frequency chirps. The 5HT2 receptor agonist DOI decreased chirping. Receptor antagonists (WAY-100635 and MDL-11939) opposed the effects of their corresponding agonists. These results suggest that serotonergic inhibition of chirping may be mediated by 5HT2 receptors, but that serotonergic activation of 5HT1A receptors specifically increases the production of high-frequency chirps. The enhancement of chirping by 5HT1A receptors may result from interactions with cortisol and/or arginine vasotocin, which similarly enhance chirping and are influenced by 5HT1A activity in other systems. 相似文献
19.
《Journal of receptor and signal transduction research》2013,33(2):99-124
All three α2-adrenoceptor subtypes have a long third intracellular loop (3i), which is conserved by overall size and charge-hydrophobic properties but not by amino acid sequence similarity. These properties must be relevant for function and structure, because they have been preserved during hundreds of millions of years of evolution. The contribution of different loop portions to agonist/antagonist binding properties and G protein coupling of the human α2B-adrenoceptor (α2B-AR) was investigated with a series of 3i truncated constructs (Δ 3i). We used a variety of agonists/antagonists in competition binding assays. We stimulated α2B-AR Δ3i with various agonists and measured [35S]GTPγS binding in isolated cell membranes with or without antagonist inhibition. We also evaluated the ability of oligopeptides, analogous to the amino and carboxyl terminal parts of 3i, to promote G protein activation, monitored with the [35S]GTPγS assay. Our results reveal that the carboxyl end residues of 3i, R360(6.24) to V372(6.36), are important for Gi/Go protein activation. Deletions in regions from G206(5.72) to R245(5.110) altered the binding of some α2B-AR agonists, indicating that agonist binding is dependent on the conformation of the 3i domain, possibly through the involvement of G protein interactions. The truncated receptor constructs may be more stable on purification and thus be useful for structural characterization of α2B-AR. 相似文献
20.
Lux-Lantos VA Bianchi MS Catalano PN Libertun C 《Cellular and molecular neurobiology》2008,28(6):803-817
Gamma-amino butyric acid (GABA), in addition to being a metabolic intermediate and the main inhibitory neurotransmitter in
the synaptic cleft, is postulated as a neurohormone, a paracrine signaling molecule, and a trophic factor. It acts through
pre- and post-synaptic receptors, named GABAA and GABAC (ionotropic receptors) and GABAB (metabotropic receptor). Here we reviewed the participation of GABAB receptors in the regulation of the hypothalamic-pituitary-gonadal axis, using physiological, biochemical, and pharmacological
approaches in rats, as well as in GABAB1 knock-out mice, that lack functional GABAB receptors. Our general conclusion indicates that GABAB receptors participate in the regulation of pituitary hormone secretion acting both in the central nervous system and directly
on the gland. PRL and gonadotropin axes are affected by GABAB receptor activation, as demonstrated in the rat and also in the GABAB1 knock-out mouse. In addition, hypothalamic and pituitary GABAB receptor expression is modulated by steroid hormones. GABA participation in the brain control of pituitary secretion through
GABAB receptors depends on physiological conditions, being age and sex critical factors.
These results indicate that patients receiving GABAB agonists/antagonists should be monitored for possible endocrine side effects. 相似文献