Adrenoceptors, α2
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PROVIDER: S-EPMC2884644 | biostudies-literature | 2009 Nov
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND AND PURPOSE Muscarinic and adrenergic G protein-coupled receptors (GPCRs) are the targets of rare peptide toxins isolated from snake or cone snail venoms. We used a screen to identify novel toxins from Dendroaspis angusticeps targeting aminergic GPCRs. These toxins may offer new candidates for the development of new tools and drugs. EXPERIMENTAL APPROACH In binding experiments with (3) H-rauwolscine, we studied the interactions of green mamba venom fractions with α(2) -adrenoceptors from rat brain synaptosomes. We isolated, sequenced and chemically synthesized a novel peptide, ρ-Da1b. This peptide was pharmacologically characterized using binding experiments and functional tests on human α(2)-adrenoceptors expressed in mammalian cells. KEY RESULTS ρ-Da1b, a 66-amino acid peptide stabilized by four disulphide bridges, belongs to the three-finger-fold peptide family. Its synthetic homologue inhibited 80% of (3) H-rauwolscine binding to the three α(2)-adrenoceptor subtypes, with an affinity between 14 and 73 nM and Hill slopes close to unity. Functional experiments on α(2A) -adrenoceptor demonstrated that ρ-Da1b is an antagonist, shifting adrenaline activation curves to the right. Schild regression revealed slopes of 0.97 and 0.67 and pA(2) values of 5.93 and 5.32 for yohimbine and ρ-Da1b, respectively. CONCLUSIONS AND IMPLICATIONS ρ-Da1b is the first toxin identified to specifically interact with α(2)-adrenoceptors, extending the list of class A GPCRs sensitive to toxins. Additionally, its affinity and atypical mode of interaction open up the possibility of its use as a new pharmacological tool, in the study of the physiological roles of α(2)-adrenoceptor subtypes.
| S-EPMC3000660 | biostudies-literature
Project description:BACKGROUND:Dihydroergotamine (DHE) is an antimigraine drug that produces cranial vasoconstriction and inhibits trigeminal CGRP release; furthermore, it inhibits the vasodepressor sensory CGRPergic outflow, but the receptors involved remain unknown. Prejunctional activation of α2A/2C-adrenergic, serotonin 5-HT1B/1F, or dopamine D2-like receptors results in inhibition of this CGRPergic outflow. Since DHE displays affinity for these receptors, this study investigated the pharmacological profile of DHE-induced inhibition of the vasodepressor sensory CGRPergic outflow. METHODS:Pithed rats were pretreated i.v. with hexamethonium (2 mg/kg·min) followed by continuous infusions of methoxamine (20 μg/kg·min) and DHE (3.1 μg/kg·min). Then, stimulus-response curves (spinal electrical stimulation; T9-T12) or dose-response curves (i.v. injections of α-CGRP) resulted in frequency-dependent or dose-dependent decreases in diastolic blood pressure. RESULTS:DHE inhibited the vasodepressor responses to electrical stimulation (0.56-5.6 Hz), without affecting those to i.v. α-CGRP (0.1-1 μg/kg). This inhibition by DHE (not produced by the methoxamine infusions): (i) was abolished by pretreatment with the combination of the antagonists rauwolscine (α2-adrenoceptor; 310 μg/kg) plus GR127935 (5-HT1B/1D; 31 μg/kg); and (ii) remained unaffected after rauwolscine (310 μg/kg), GR127935 (31 μg/kg) or haloperidol (D2-like; 310 μg/kg) given alone, or after the combination of rauwolscine plus haloperidol or GR127935 plus haloperidol at the aforementioned doses. CONCLUSION:DHE-induced inhibition of the vasodepressor sensory CGRPergic outflow is mainly mediated by prejunctional rauwolscine-sensitive α2-adrenoceptors and GR127935-sensitive 5-HT1B/1D receptors, which correlate with α2A/2C-adrenoceptors and 5-HT1B receptors, respectively. These findings suggest that DHE-induced inhibition of the perivascular sensory CGRPergic outflow may facilitate DHE's vasoconstrictor properties resulting in an increased vascular resistance.
| S-EPMC5970131 | biostudies-literature
Project description:We quantified the binding potentials (BPND) of [(11)C]yohimbine binding in rat brain to alpha-2 adrenoceptors to evaluate [(11)C]yohimbine as an in vivo marker of noradrenergic neurotransmission and to examine its sensitivity to the level of noradrenaline. Dual [(11)C]yohimbine dynamic positron emission tomography (PET) recordings were applied to five Sprague Dawley rats at baseline, followed by acute amphetamine administration (2 mg/kg) to induce elevation of the endogenous level of noradrenaline. The volume of distribution (VT) of [(11)C]yohimbine was obtained using Logan plot with arterial plasma input. Because alpha-2 adrenoceptors are distributed throughout the brain, the estimation of the BPND is complicated by the absence of an anatomic region of no displaceable binding. We used the Inhibition plot to acquire the reference volume, VND, from which we calculated the BPND. Acute pharmacological challenge with amphetamine induced a significant decline of [(11)C]yohimbine BPND of ~38% in all volumes of interest. The BPND was greatest in the thalamus and striatum, followed in descending order by, frontal cortex, pons, and cerebellum. The experimental data demonstrate that [(11)C]yohimbine binding is sensitive to a challenge known to increase the extracellular level of noradrenaline, which can benefit future PET investigations of pathologic conditions related to disrupted noradrenergic neurotransmission.
| S-EPMC4348393 | biostudies-other
Project description:Background and purposeAgmatine, a putative neurotransmitter, plays a vital role in learning and memory. Although it is considered an endogenous ligand of imidazoline receptors, agmatine exhibits high affinity for α-adrenoceptors, NOS and NMDA receptors. These substrates within the locus coeruleus (LC) are critically involved in learning and memory processes.Experimental approachThe hippocampus and LC of male Wistar rat were stereotaxically cannulated for injection. Effects of agmatine, given i.p. or intra-LC, on acquisition, consolidation and retrieval of inhibitory avoidance (IA) memory were measured. The NO donor S-nitrosoglutathione, non-specific (L-NAME) and specific NOS inhibitors (L-NIL, 7-NI, L-NIO), the α2 -adrenoceptor antagonist (yohimbine) or the corresponding agonist (clonidine) were injected intra-LC before agmatine. Intra-hippocampal injections of the NMDA antagonist, MK-801 (dizocilpine), were used to modify the memory enhancing effects of agmatine, SNG and yohimbine. Expression of tyrosine hydroxylase (TH) and eNOS in the LC was assessed immunohistochemically.Key resultsAgmatine (intra-LC or i.p.) facilitated memory retrieval in the IA test. S-nitrosoglutathione potentiated, while L-NAME and L-NIO decreased, these effects of agmatine. L-NIL and 7-NI did not alter the effects of agmatine. Yohimbine potentiated, whereas clonidine attenuated, effects of agmatine within the LC. The effects of agmatine, S-nitrosoglutathione and yohimbine were blocked by intra-hippocampal MK-801. Agmatine increased the population of TH- and eNOS-immunoreactive elements in the LC.Conclusions and implicationsThe facilitation of memory retrieval in the IA test by agmatine is probably mediated by interactions between eNOS, NO and noradrenergic pathways in the LC.
| S-EPMC4978159 | biostudies-literature
Project description: Not available
| S-EPMC4235180 | biostudies-literature
Project description:BackgroundThere are three turkey β-adrenoceptors: the original turkey β-adrenoceptor from erythrocytes (tβtrunc, for which the X-ray crystal structure has recently been determined), tβ3C and tβ4C-receptors. This study examined the similarities and differences between these avian receptors and mammalian receptors with regards to binding characteristics and functional high and low affinity agonist conformations.Methodology/principal findingsStable cell lines were constructed with each of the turkey β-adrenoceptors and 3H-CGP12177 whole cell binding, CRE-SPAP production and (3)H-cAMP accumulation assays performed. It was confirmed that the three turkey β-adrenoceptors are distinct from each other in terms of amino acid sequence and binding characteristics. The greatest similarity of any of the turkey β-adrenoceptors to human β-adrenoceptors is between the turkey β3C-receptor and the human β2-adrenoceptor. There are pharmacologically distinct differences between the binding of ligands for the tβtrunc and tβ4C and the human β-adrenoceptors (e.g. with CGP20712A and ICI118551). The tβtrunc and tβ4C-adrenoceptors appear to exist in at least two different agonist conformations in a similar manner to that seen at both the human and rat β1-adrenoceptor and human β3-adrenoceptors. The tβ3C-receptor, similar to the human β2-adrenoceptor, does not, at least so far, appear to exist in more than one agonist conformation.Conclusions/significanceThere are several similarities, but also several important differences, between the recently crystallised turkey β-adrenoceptor and the human β-adrenoceptors. These findings are important for those the field of drug discovery using the recently structural information from crystallised receptors to aid drug design. Furthermore, comparison of the amino-acid sequence for the turkey and human adrenoceptors may therefore shed more light on the residues involved in the existence of the secondary β-adrenoceptor conformation.
| S-EPMC2994877 | biostudies-literature
Project description:Background and purposeIntact endothelium plays a pivotal role in post-ischaemic angiogenesis. It is a phenomenon finely tuned by activation and inhibition of several endothelial receptors. The presence of alpha(1)-adrenoceptors on the endothelium suggests that these receptors may participate in regenerative phenomena by regulating the responses of endothelial cells involved in neo-angiogenesis.Experimental approachWe evaluated the expression of the subtypes of the alpha(1)-adrenoceptor in isolated endothelial cells harvested from Wistar-Kyoto (WKY) rats. We explored the possibility these alpha(1)-adrenoceptors may influence the pro-angiogenic phenotype of endothelial cells in vitro. In vivo, we used a model of hindlimb ischaemia in WKY rats, to assess the effects of alpha(1) adrenoceptor agonist or antagonist on angiogenesis in the ischaemic hindlimb by laser Doppler blood flow measurements, digital angiographies, hindlimb perfusion with dyed beads and histological evaluation.Key resultsIn vitro, pharmacological antagonism of alpha(1)-adrenoceptors in endothelial cells from WKY rats by doxazosin enhanced, while stimulation of these adrenoceptors with phenylephrine, inhibited endothelial cell proliferation and DNA synthesis, ERK and retinoblastoma protein (Rb) phosphorylation, cell migration and tubule formation. In vivo, we found increased alpha(1)-adrenoceptor density in the ischaemic hindlimb, compared to non-ischaemic hindlimb, suggesting an enhanced alpha(1)-adrenoceptor tone in the ischaemic tissue. Treatment with doxazosin (0.06 mg kg(-1) day(-1) for 14 days) did not alter systemic blood pressure but enhanced neo-angiogenesis in the ischaemic hindlimb, as measured by all our assays.ConclusionsOur findings support the hypothesis that the alpha(1)-adrenoceptors in endothelial cells provide a negative regulation of angiogenesis.
| S-EPMC2267280 | biostudies-literature
Project description:Stress plays a role in tumourigenesis through catecholamines acting at β-adrenoceptors including β1 -, β2 - and β3 -adrenoceptors, and the use of β-adrenoceptor antagonists seems to counteract tumour growth and progression. Preclinical evidence and meta-analysis data demonstrate that melanoma shows a positive response to β-adrenoceptor blockers and in particular to propranolol acting mainly at β1 - and β2 -adrenoceptors. Although evidence suggesting that β3 -adrenoceptors may play a role as a therapeutic target in infantile haemangiomas has been recently reviewed, a comprehensive analysis of the data available from preclinical studies supporting a possible role of β3 -adrenoceptors in melanoma was not available. Here, we review data from the literature demonstrating that propranolol may be effective at counteracting melanoma growth, and we provide preclinical evidence that β3 -adrenoceptors may also play a role in the pathophysiology of melanoma, thus opening the door for further clinical assays trying to explore β3 -adrenoceptor blockers as novel alternatives for its treatment. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.
| S-EPMC6592869 | biostudies-literature