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1.
Background
Taurine is one of the most abundant free amino acids especially in excitable tissues, with wide physiological actions. Chronic supplementation of taurine in drinking water to mice increases brain excitability mainly through alterations in the inhibitory GABAergic system. These changes include elevated expression level of glutamic acid decarboxylase (GAD) and increased levels of GABA. Additionally we reported that GABAA receptors were down regulated with chronic administration of taurine. Here, we investigated pharmacologically the functional significance of decreased / or change in subunit composition of the GABAA receptors by determining the threshold for picrotoxin-induced seizures. Picrotoxin, an antagonist of GABAA receptors that blocks the channels while in the open state, binds within the pore of the channel between the β2 and β3 subunits. These are the same subunits to which GABA and presumably taurine binds.Methods
Two-month-old male FVB/NJ mice were subcutaneously injected with picrotoxin (5 mg kg-1) and observed for a) latency until seizures began, b) duration of seizures, and c) frequency of seizures. For taurine treatment, mice were either fed taurine in drinking water (0.05%) or injected (43 mg/kg) 15 min prior to picrotoxin injection.Results
We found that taurine-fed mice are resistant to picrotoxin-induced seizures when compared to age-matched controls, as measured by increased latency to seizure, decreased occurrence of seizures and reduced mortality rate. In the picrotoxin-treated animals, latency and duration were significantly shorter than in taurine-treated animas. Injection of taurine 15 min before picrotoxin significantly delayed seizure onset, as did chronic administration of taurine in the diet. Further, taurine treatment significantly increased survival rates compared to the picrotoxin-treated mice.Conclusions
We suggest that the elevated threshold for picrotoxin-induced seizures in taurine-fed mice is due to the reduced binding sites available for picrotoxin binding due to the reduced expression of the beta subunits of the GABAA receptor. The delayed effects of picrotoxin after acute taurine injection may indicate that the two molecules are competing for the same binding site on the GABAA receptor. Thus, taurine-fed mice have a functional alteration in the GABAergic system. These include: increased GAD expression, increased GABA levels, and changes in subunit composition of the GABAA receptors. Such a finding is relevant in conditions where agonists of GABAA receptors, such as anesthetics, are administered.2.
We studied the effect of furosemide on GABAA-induced 36Cl transport and GABAA-induced Cl--ATPase activity in synaptic membranes of fish brain. At physiological pH 7.4, GABA (0.1–100 µM) stimulated 36Cl influx in synaptoneurosomes and Cl--ATPase activity in synaptic membranes. Furosemide (0.1–0.5 mM) removed the activating effect of the mediator on chloride transport and enzyme activity (I50 equaled 0.16 and 0.12 mM, respectively). In the absence of the mediator, picrotoxin (50 µM) activated the basal 36Cl influx in synaptoneurosomes and the basal Mg2+-ATPase activity of synaptic membranes. Furosemide (1 mM) removed the activating effect of picrotoxin on both biochemical processes. The obtained data demonstrated similar sensitivities of GABAA-induced transport of 36Cl in synaptoneurosomes and of GABAA-induced Cl--ATPase activity in the synaptic membranes to furosemide and indicated the involvement of the ATPase in GABAA-induced processes. The soluble ATPase, recovered by sodium deoxycholate solubilization of the membranes, remained sensitive to GABAA-ergic ligands, which suggested proximity of their binding sites with ATP hydrolysis sites in the protein molecule and their structural coupling.Translated from Izvestiya Akademii Nauk, Seriya Biologicheskaya, No. 1, 2005, pp. 18–22.Original Russian Text Copyright © 2005 by Menzikov, Menzikova. 相似文献
3.
Harsahay Meena Kartik T. Nakhate Dadasaheb M. Kokare Nishikant K. Subhedar 《Life sciences》2009,84(5-6):156-163
AimsWeight gain is a common outcome of antipsychotics therapy in schizophrenic patients. However, the underlying neuronal mechanisms are unclear. The present study was undertaken to investigate the role of GABAA receptors within the framework of nucleus accumbens shell (AcbSh) in haloperidol-induced hyperphagia and body weight gain in sated rats.Main methodsIn acute studies, GABAA receptor agonists muscimol, diazepam or antagonist bicuculline were administered by AcbSh route, alone or in combination with haloperidol (intraperitoneal/ip). Immediately after these treatments, preweighed food was offered to the animals at commencement of dark phase. Cumulative food intake was measured at 2 and 6 h post-injection time-points. Furthermore, effects of subacute haloperidol treatment, alone or in combination with muscimol, diazepam or bicuculline, on food intake and body weight were investigated.Key findingsWhile acute treatment with haloperidol, muscimol or diazepam dose dependently stimulated the food intake, bicuculline suppressed the same. Prior administration of muscimol (20 ng/rat, intra-AcbSh) and diazepam (5 µg/rat, intra-AcbSh) significantly potentiated, whereas bicuculline (40 ng/rat, intra-AcbSh) negated the hyperphagic effect of acute haloperidol (0.005 or 0.01 mg/kg/rat, ip). Subacute administration of haloperidol (0.01 mg/kg/rat/day, ip) for 15 days produced increase in food intake and body weight. Although, concomitant administration of muscimol (20 ng/rat/day, intra-AcbSh) or diazepam (5 μg/rat/day, intra-AcbSh) markedly enhanced, bicuculline (40 ng/rat/day, intra-AcbSh) prevented the subacute haloperidol-induced hyperphagia and weight gain.SignificanceThe results of present study suggest that increased food intake and body weight following haloperidol treatment in rats, may be mediated via AcbSh GABAA receptors. 相似文献
4.
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
5.
The flunitrazepam sensitive-GABAA receptor density was increased by cytochalasins C and D at 37°C suggesting that microfilament depolymerization induces exposure
to the radioligand of a GABAA receptor in synaptosomes (Pharm Biochem Behav 72 (2002) 497). Similarly, phosphatidylinositol-4,5-bisphosphate (1–5 μM),
but not a mixture of phospholipids, induced an increase of GABAA receptors in synaptosomes. Furthermore, N-ethyl maleimide, an inactivator of the sensitive fusion protein, which interacts
with GABAA receptor, abolished the receptor increase induced by phosphatidylinositol-4,5-bisphosphate. Together, the results suggest
that phosphatidylinositol-4,5-bisphosphate, acts via microfilament depolymerization increasing the binding of the radioligand
to receptors possibly by modulation of their interaction with proteins involved in trafficking and docking mechanisms. 相似文献
6.
Nociceptin/orphanin FQ (N/OFQ) and nocistatin are two neuropeptides originated from the same precursor prepronociceptin/orphanin FQ (ppN/OFQ). N/OFQ is the endogenous ligand of the NOP receptor, while the target of action of nocistatin is still unknown. N/OFQ modulates various biological functions, including anxiety. Conversely, nocistatin either behaves as a functional N/OFQ antagonist or evokes per se effects opposite to those of N/OFQ. Here we investigated the interaction between the anxiolytic-like effects of N/OFQ and the anxiogenic-like action of nocistatin with those evoked by GABAA receptor ligands in the mouse elevated plus maze. The anxiogenic-like effects of the GABAA receptor antagonist pentylenetetrazol (20 mg/kg; intraperitoneal, i.p.) were abolished by the co-treatment with N/OFQ (10 pmol; intracerebroventricular, i.c.v.) while potentiated by the administration of nocistatin (0.01 pmol; i.c.v.). The anxiolytic-like effects of the benzodiazepine receptor agonist diazepam (0.75 mg/kg, i.p.) were reversed by nocistatin (0.1 pmol; i.c.v.), whereas signs of sedation were observed when mice were co-treated with diazepam and N/OFQ (3 pmol). Interesting enough, the i.p. treatment with flumazenil (1 mg/kg) blocked the anxiolytic-like effects of N/OFQ (10 pmol; i.c.v.), but not the anxiogenic effect elicited by nocistatin. Collectively, our findings suggest that the effects on anxiety elicited by pentylenetetrazol and diazepam can be counteracted or potentiated in the presence of N/OFQ and nocistatin. In addition, the effects on anxiety of N/OFQ, but not nocistatin, appear to be dependent on the benzodiazepine site of the GABAA receptor. 相似文献
7.
GABA triggers mammalian sperm acrosome reaction (AR). Here, evidence is presented, showing that rat spermatozoa contain GABAA receptors, composed of 5, 1 and 3 subunits. The effects of GABAA receptor agonist and antagonist on the induction of AR in rat spermatozoa were assessed using the chlortetracycline assay. Muscimol, a GABAA receptor agonist, triggered AR; whereas bicuculline, a GABAA receptor antagonist and picrotoxin, a GABAA receptor/Cl– channel blocker, inhibited the ability of GABA or progesterone to induce AR. In conclusion, GABAA receptors appear to mediate the action of progesterone in inducing AR in rat spermatozoa. 相似文献
8.
Wheeler DW Thompson AJ Corletto F Reckless J Loke JC Lapaque N Grant AJ Mastroeni P Grainger DJ Padgett CL O'Brien JA Miller NG Trowsdale J Lummis SC Menon DK Beech JS 《PloS one》2011,6(2):e17152
Background
GABAA receptors are members of the Cys-loop family of neurotransmitter receptors, proteins which are responsible for fast synaptic transmission, and are the site of action of wide range of drugs [1]. Recent work has shown that Cys-loop receptors are present on immune cells, but their physiological roles and the effects of drugs that modify their function in the innate immune system are currently unclear [2]. We are interested in how and why anaesthetics increase infections in intensive care patients; a serious problem as more than 50% of patients with severe sepsis will die [3]–[6]. As many anaesthetics act via GABAA receptors [7], the aim of this study was to determine if these receptors are present on immune cells, and could play a role in immunocompromising patients.Principal Findings
We demonstrate, using RT-PCR, that monocytes express GABAA receptors constructed of α1, α4, β2, γ1 and/or δ subunits. Whole cell patch clamp electrophysiological studies show that GABA can activate these receptors, resulting in the opening of a chloride-selective channel; activation is inhibited by the GABAA receptor antagonists bicuculline and picrotoxin, but not enhanced by the positive modulator diazepam. The anaesthetic drugs propofol and thiopental, which can act via GABAA receptors, impaired monocyte function in classic immunological chemotaxis and phagocytosis assays, an effect reversed by bicuculline and picrotoxin.Significance
Our results show that functional GABAA receptors are present on monocytes with properties similar to CNS GABAA receptors. The functional data provide a possible explanation as to why chronic propofol and thiopental administration can increase the risk of infection in critically ill patients: their action on GABAA receptors inhibits normal monocyte behaviour. The data also suggest a potential solution: monocyte GABAA receptors are insensitive to diazepam, thus the use of benzodiazepines as an alternative anesthetising agent may be advantageous where infection is a life threatening problem. 相似文献9.
Norimasa Kanegawa 《FEBS letters》2010,584(3):599-2362
We found that Tyr-Leu (YL) dose-dependently exhibits potent anxiolytic-like activity (0.1-1 mg/kg, i.p.) comparable to diazepam in the elevated plus-maze test in mice. YL was orally active (0.3-3 mg/kg). A retro-sequence peptide or a mixture of Tyr and Leu was inactive. The anxiolytic-like activity of YL was inhibited by antagonists for serotonin 5-HT1A, dopamine D1 and GABAA receptors; however, YL had no affinity for them. We also determined the order of their activation is 5-HT1A, D1 and GABAA receptors using selective agonists and antagonists. Taken together, YL may exhibit anxiolytic-like activity via activation of 5-HT1A, D1 and GABAA receptors. 相似文献
10.
General anesthetics thiopental and pentobarbital possess very similar chemical structures whereas their clinical potency is
quite different. The underlying molecular mechanism is not fully understood. This study was designed to assess the differential
effects of thiopental and pentobarbital on GABAA receptors of mechanically dissociated rat spinal dorsal horn neurons by using whole-cell patch-clamp technique. Pentobarbital,
at a concentration of 30 μM, which markedly enhanced sub-saturated GABA-induced current (I
GABA), had no effect on thiopental-induced maximal current. Similarly, the pentobarbital-induced maximal current was also not
affected by 30 μM thiopental. Moreover, a linear summation of thiopental-induced maximal current and pentobarbital-induced
sub-maximal current was observed. In addition, pentobarbital failed to further enhance I
GABA in the presence of thiopental at a concentration with maximal modulatory effects on I
GABA, and vice versa. Our results thus suggest that thiopental and pentobarbital might exert the GABA mimetic effects independently,
but share a common mechanism to produce the GABA modulatory effects.
Special issue article in honor of Dr. Ji-Sheng Han. 相似文献
11.
The neurotransmitter gamma-aminobutyric acid (GABA) and subtypes of GABA receptors were recently identified in adult testes. Since adult Leydig cells possess both the GABA biosynthetic enzyme glutamate decarboxylase (GAD), as well as GABAA and GABAB receptors, it is possible that GABA may act as auto-/paracrine molecule to regulate Leydig cell function. The present study was aimed to examine effects of GABA, which may include trophic action. This assumption is based on reports pinpointing GABA as regulator of proliferation and differentiation of developing neurons via GABAA receptors. Assuming such a role for the developing testis, we studied whether GABA synthesis and GABA receptors are already present in the postnatal testis, where fetal Leydig cells and, to a much greater extend, cells of the adult Leydig cell lineage proliferate. Immunohistochemistry, RT-PCR, Western blotting and a radioactive enzymatic GAD assay evidenced that fetal Leydig cells of five-six days old rats possess active GAD protein, and that both fetal Leydig cells and cells of the adult Leydig cell lineage possess GABAA receptor subunits. TM3 cells, a proliferating mouse Leydig cell line, which we showed to possess GABAA receptor subunits by RT-PCR, served to study effects of GABA on proliferation. Using a colorimetric proliferation assay and Western Blotting for proliferating cell nuclear antigen (PCNA) we demonstrated that GABA or the GABAA agonist isoguvacine significantly increased TM3 cell number and PCNA content in TM3 cells. These effects were blocked by the GABAA antagonist bicuculline, implying a role for GABAA receptors. In conclusion, GABA increases proliferation of TM3 Leydig cells via GABAA receptor activation and proliferating Leydig cells in the postnatal rodent testis bear a GABAergic system. Thus testicular GABA may play an as yet unrecognized role in the development of Leydig cells during the differentiation of the testicular interstitial compartment. 相似文献
12.
GABAA receptor-associated protein (GABARAP) is a 14-kDa cytoplasmic protein initially identified as a molecular chaperone for GABAA receptor in cortical neurons. However, evidence indicates that the function of GABARAP is much broader than a specific role in neuronal cells. As an initial step to define the biological role of GABARAP, we searched for binding partners of GABARAP using co-immunoprecipitation coupled with LC-MS/MS analysis. As a result, DEAD (Asp-Glu-Ala-Asp/His) box polypeptide 47 (DDX 47), recently identified as RNA helicase, is identified as a binding partner of GABARAP. An interaction between GABARAP and DDX 47 was further confirmed by yeast two-hybrid systems. Further, co-transfection of GABARAP and DDX47 cDNA into a tumor cell line induces apoptosis. This result may be the first evidence showing that GABARAP and DDX 47 are involved in the apoptotic process. 相似文献
13.
P A Polo R O Reis P L Cedraz-Mercez H R Cavalcante-Lima E L Olivares M A Medeiros W S C?rtes L C Reis 《Revista brasleira de biologia》2007,67(1):167-171
This study was carried out aiming to reach behavioral and neuropharmacological evidence of the permeability of the blood-brain barrier (BBB) to serotonin systemically administered in quails. Serotonin injected by a parenteral route (250-1000 microg x kg(-1), sc) elicited a sequence of behavioral events concerned with a sleeping-like state. Sleeping-like behaviors began with feather bristling, rapid oral movements, blinking and finally crouching and closure of the eyes. Previous administration of 5-HT2C antagonist, LY53857 (3 mg x kg(-1), sc) reduced the episodes of feather bristling and rapid oral movements significantly but without altering the frequency of blinking and closure of the eyes. Treatment with the 5-HT2A/2C antagonist, ketanserin (3 mg x kg(-1), sc) did not affect any of the responses evoked by the serotonin. Quipazine (5 mg x kg(-1), sc) a 5-HT2A/2C/3 agonist induced intense hypomotility, long periods of yawning-like and sleeping-like states. Previous ketanserin suppressed gaping responses and reduced hypomotility, rapid oral movements and bristling but was ineffective for remaining responses induced by quipazine. Results showed that unlike mammals, serotonin permeates the BBB and activates hypnogenic mechanisms in quails. Studies using serotoninergic agonist and antagonists have disclosed that among the actions of the serotonin, feather bristling, rapid oral movements and yawning-like state originated from activation of 5-HT2 receptors while blinking and closure of the eyes possibly require other subtypes of receptors. 相似文献
14.
Intracellular recordings were made from amacrine cells in the isolated, superfused carp retina, and the effects of γ-aminobutyric acid (GABA) on sustained and transient ON signals of these cells were studied. Exogenous GABA application partially suppressed the sustained response of ON amacrine cells, which could be completely reversed by picrotoxin (PTX), a chloride channel blocker, and by bicuculline (BCC), a specific GABA_A receptor antagonist. On the other hand, suppression by GABA of the ON response which was predominantly driven by rod signals in a certain portion of transient ON-OFF amacrine cells was completely blocked by PTX, but not by BCC, indicating that GABA_C receptors may be involved in the effect. These results suggest that GABA_A and GABA_C receptors may be respectively involved in mediating the transmission of sustained and transient signals in the carp inner retina. 相似文献
15.
González Ramírez M Orozco Suárez S Salgado Ceballos H Feria Velasco A Rocha L 《Cellular and molecular neurobiology》2007,27(2):211-227
Effects of hyperthermia-induced seizures (HS) on GABAA and benzodiazepine (BDZ) receptor binding in immature rat brain were evaluated using in vitro autoradiography. HS were induced
in 10-days-old rats by a regulated stream of moderately heated air directed 50 cm above the animals. Rats were killed 30 min,
24 h or 20 days after HS and their brains were used for in vitro autoradiography experiments to determine GABAA and BDZ receptor binding. GABAA binding was significantly enhanced in all brain areas evaluated 30 min after HS, an effect that endures 24 h and 20 days
after seizures. Concerning BDZ receptor binding, a significant increase was detected in entorhinal and perirhinal cortices
and decreased in basolateral amygdala 30 min following HS. One day after HS, animals demonstrated enhanced BDZ binding in
the cingulate, frontal, posterior parietal, entorhinal, temporal and perirhinal cortices; striatum, accumbens, substantia
nigra pars compacta and amygdala nuclei. Twenty days after HS enhanced BDZ binding was restricted in the cingulated, frontal,
anterior and posterior parietal cortices, as well as in substantia nigra pars reticulata, whereas decreased values were found
in accumbens nucleus and substantia nigra pars compacta. Our data indicate differential effects of HS in GABAA and BDZ binding in immature brain. HS-induced GABAA and BDZ changes are different from those previously described in experimental models of temporal lobe epilepsy in adult animals. 相似文献
16.
Morteza Zendehdel Ali Baghbanzadeh Vahab Babapour Javad Cheraghi 《Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology》2009,195(8):715-720
This study was designed to examine the effects of intracerebroventricular (ICV) injection of bicuculline (GABAA receptor antagonist) and muscimol (GABAA receptor agonist) on glutamate-induced eating response in 24-h food-deprived (FD24) broiler cockerels. At first, guide cannula
was surgically implanted in the right lateral ventricle of chickens. In experiment 1, birds were ICV injected with different
doses of glutamate. In experiment 2, birds were administered with effective dose of glutamate after bicuculline. In experiment
3, chickens received muscimol prior to the injection of glutamate, and cumulative food intake was determined at 3-h postinjection.
The results of this study showed that glutamate decreases food consumption in FD24 broiler cockerels (P ≤ 0.05), and this reduction occurs in a dose-dependent manner. Moreover, the inhibitory effect of glutamate on food intake
was significantly increased with bicuculline pretreatment, and this effect was attenuated with muscimol (P ≤ 0.05). These results suggest that there is an interaction between glutamatergic and GABAergic systems (through GABAA receptor) on food intake in broiler cockerels. 相似文献
17.
González-Ramírez M Orozco S Salgado H Feria A Rocha L 《Cellular and molecular neurobiology》2005,25(6):955-971
Summary Effects of hyperthermia-induced seizures (HS) on GABAA and benzodiazepine (BDZ) receptor binding in immature rat brain were evaluated using in vitro autoradiography. HS were induced in 10-day-old rats by a regulated stream of moderately heated air directed 50 cm above the
animals. Rats were killed 30 min, 24 h, or 20 days after HS and their brains were used for in vitro autoradiography experiments to determine GABAA and BDZ receptor binding. GABAA binding was significantly enhanced in all brain areas evaluated 30 min after HS, an effect that endures 24 h and 20 days
after seizures. Concerning BDZ receptor binding, a significant increase was detected in entorhinal and perirhinal cortices
and decreased in basolateral amygdala 30 min following HS. One day after HS, animals demonstrated enhanced BDZ binding in
the cingulate, frontal, posterior parietal, entorhinal, temporal, and perirhinal cortices; striatum, accumbens, substantia
nigra pars compacta, and amygdala nuclei. Twenty days after HS enhanced BDZ binding was restricted in the cingulated, frontal,
anterior and posterior parietal cortices, as well as in substantia nigra pars reticulata, whereas decreased values were found
in accumbens nucleus and substantia nigra pars compacta. Our data indicate differential effects of HS in GABAA and BDZ binding in immature brain. HS-induced GABAA and BDZ changes are different from those previously described in experimental models of temporal lobe epilepsy in adult animals. 相似文献
18.
One of the many pharmacological targets of ethanol is the GABA inhibitory system, and chronic ethanol (CE) is known to alter
the polypeptide levels of the GABAA receptor subunits in rat brain regions. In the present study, we investigated the regulation of the tyrosine kinase phosphorylation
of the GABAA receptor α1-, β2- and γ2-subunits in the rat cerebellum, cerebral cortex and hippocampus following chronic administration of ethanol to the rats.
We observed either down-regulation or no change in the tyrosine kinase phosphorylation of the α1 subunit, whereas there was an up-regulation or no change in the case of β2- and γ2-subunits of the GABAA receptors depending on the brain region following chronic administration of ethanol to the rats. These changes reverted back
to the control level following 48 h of ethanol-withdrawal. These results suggest that tyrosine kinase phosphorylation of GABAA receptors may play a significant role in ethanol dependence. 相似文献
19.
Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named
A1, A2A, A2B and A3 (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A2B AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding
of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A2B AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective
agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview
of the recent advancements in identifying potent and selective A2B AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine
ligands. Nucleoside-based agonists are the result of modifying adenosine by substitution at the N
6-, C2-positions of the purine heterocycle and/or at the 5′-position of the ribose moiety or combinations of these substitutions.
Compounds 1-deoxy-1-{6-[N′-(furan-2-carbonyl)-hydrazino]-9H-purin-9-yl}-N-ethyl-β-D-ribofuranuronamide (19, hA1
K
i = 1050 nM, hA2A
K
i = 1550 nM, hA2B EC50 = 82 nM, hA3
K
i > 5 μM) and its 2-chloro analogue 23 (hA1
K
i = 3500 nM, hA2A
K
i = 4950 nM, hA2B EC50 = 210 nM, hA3
K
i > 5 μM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay
in Chinese hamster ovary (CHO) cells expressing hA2B AR. Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide
(BAY-60–6583, hA1, hA2A, hA3 EC50 > 10 μM; hA2B EC50 = 3 nM) is currently under preclinical-phase investigation for treating coronary artery disorders and atherosclerosis. 相似文献
20.
Effect of avermectin (AVM) on the expression of γ‐aminobutyric acid A receptor (GABAAR) in Carassius gibelio (Bloch, 1782)
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A. L. Zhou K. Hu J. M. Ruan H. P. Cao Y. Wang Y. N. Zhao X. L. Yang 《Zeitschrift fur angewandte Ichthyologie》2015,31(5):862-869
This study describes the effect of avermectin (AVM) on the expression of γ‐aminobutyric acid A receptor (GABAAR) in Carassius gibelio. To assess the specific expression of GABAAR in the brain, gonads, liver, kidneys, heart, muscles, and skin of C. gibelio, the expression of GABAAR α1 subunit (GABAARα1) was measured by Western blotting. To study the effects of AVM on the expression of GABAAR, the median lethal concentration (LC50) at 24, 48, and 96 h of AVM was determined and the expression of GABAAR in the brain, liver, and kidneys of the corresponding C. gibelio evaluated by Western blotting and immunohistochemistry. The results show that GABAAR was expressed in the brain, gonads, liver, kidneys, heart, intestines, muscles, and skin, while primarily distributed in the central nervous system and moderately distributed in peripheral tissues. The expression of GABAAR in the brain, liver, and kidney tissues of C. gibelio was increased with the treatment of AVM at 24 h LC50, but attenuated by the treatment of AVM at 48 h LC50 and 96 h LC50. This suggests a threshold effect of AVM. 相似文献