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At least 19 recordsLinked to original sources
PubMed1994

Cloning, expression and characterization of human alpha adrenergic receptors alpha 1a, alpha 1b and alpha 1c.

The three human alpha adrenergic receptor subtypes, alpha 1a, alpha 1b, and alpha 1c, have been cloned, expressed in COS-7 cells, and characterized pharmacologically. Competition binding studies of several adrenergic ligands with the three human receptor subtypes reveals a distinct pharmacological profile for each receptor subtype. RNase protection analysis demonstrates that the three receptor subtypes have different patterns of distribution in human tissue. The availability of the three human alpha 1 receptor subtypes will facilitate the development of subtype-selective alpha 1 antagonists for a variety of therapeutic indications.

Amino Acid Sequence↗
PubMed2004

Alpha-adrenergic receptor (alpha(2 A )) is colocalized in basal forebrain cholinergic neurons: a light and electron microscopic double immunolabeling study.

A variety of data suggest that noradrenaline and acetylcholine may interact in the basal forebrain, however no morphological studies have addressed whether indeed cholinergic neurons express adrenergic receptors. We have investigated the presence of alpha-adrenergic receptor subtype alpha2A-AR in cholinergic neurons of the basal forebrain. Cholinergic neurons were identified with an antibody against choline acetyltransferase and the receptor with a polyclonal antibody raised against a 47 amino acid fragment of the third intracellular loop of the alpha2A-AR. For double labeling at the light microscopic level the Ni-DAB/DAB technique was used, and for electron microscopy an immunoperoxidase/immunogold method was applied. We detected the alpha2A-AR protein in cholinergic as well as in non-cholinergic neurons. Almost half of all cholinergic neurons contained this adrenergic receptor. Double-labeled neurons were distributed throughout the rostro-caudal extent of the basal forebrain cholinergic continuum, including the medial septum, vertical and horizontal diagonal band nuclei, pallidal regions, substantia innominata and the internal capsule. Non-cholinergic neurons that expressed the alpha2A-AR outnumbered cholinergic/alpha2A-AR neurons by several factors. Electron microscopy confirmed the presence of alpha2A-AR in cholinergic neurons in the medial septum, vertical and horizontal diagonal band nuclei. Gold particles (10 nm) indicative of alpha2A-AR were diffusely distributed in the cytoplasm and accumulated in cytoplasmic areas near the Golgi complex and cysterns of the endoplasmic reticulum and were associated with the cellular membranes at synaptic and non-synaptic locations. Since many of the alpha2A-AR+/non-cholinergic neurons we detected are likely to be GABAergic cells, our data support the hypothesis that noradrenaline may act via basal forebrain cholinergic and non-cholinergic neurons to influence cortical activity.

Acetylcholine↗
PubMed1989

Structure and function of alpha-adrenergic receptors.

Alpha 1- and alpha 2-adrenergic receptors are the initial recognition sites on a wide variety of catecholamine-responsive target cells. This article addresses several major questions related to subtypes, structure, signal transduction mechanisms, and regulation of alpha 1- and alpha 2-adrenergic receptors. The application of biochemical and cell and molecular biologic techniques has provided many new insights regarding alpha-adrenergic receptors. Two (and perhaps three) distinct alpha 2-adrenergic receptor subtypes have been identified, and subtypes may exist for alpha 1-adrenergic receptors as well. These multiple subtypes imply much greater diversity among alpha-adrenergic receptors than among beta-adrenergic receptors. Alpha-adrenergic receptors are membrane glycoproteins with several common structural features (including seven membrane-spanning domains with extracellular amino terminus and intracellular carboxyl terminus) that are shared with other types of membrane receptors linked to guanine nucleotide-binding regulatory (G) proteins. These G proteins appear to link alpha-adrenergic receptors to multiple effector systems, including enzymes such as adenylate cyclase and phospholipases, and ion channels. The receptors themselves are dynamic entities, the number of which is regulated as a consequence of a poorly understood life cycle. Although unproven, it seems likely that several important clinical disorders represent alterations in alpha-adrenergic receptors themselves or in the G proteins or effector systems to which these receptors couple. New tools for studying receptor structure and function should help clarify the numerous, inadequately understood issues regarding alpha-adrenergic receptors and their possible alteration in disease states.

Affinity Labels↗
PubMedDate not supplied

Immunologic phagocytosis by macrophages: effect by stimulation of alpha adrenergic receptors.

Alpha adrenergic stimulating drugs, metaraminol, norepinephrine, phenylephrine, was found to increase, in vitro, immunological phagocytosis by mice peritoneal macrophages. This effect could be inhibited by dibenamine, a blocking agent. The stimulation by alpha adrenergic agents was similar to that caused by drugs that reduce the intracellular levels of cyclic adenosine monophosphate or by drugs that increase the levels of cyclic guanosine monophosphate.

Adrenergic alpha-Agonists↗
PubMed1985

Heterogeneity of alpha-2 adrenergic receptors.

Alpha adrenergic receptors are subdivided into alpha-1 and alpha-2 subtypes on the basis of their pharmacologic properties. An evaluation of data from radioligand binding and functional experiments indicates that the receptors classified as alpha-2 are not a homogeneous group. The best example of this heterogeneity is the differences in the pharmacologic properties of alpha-2 receptors in rodent and non-rodent mammalian species. Prazosin generally has a high affinity for rodent alpha-2 receptors, but a low affinity for non-rodent alpha-2 receptors, while oxymetazoline is more potent at non-rodent alpha-2 receptors. A definition of alpha-2 adrenergic receptor subtypes is proposed with prazosin having a lower affinity (200-300 nM) at alpha-2A receptors and a higher affinity (5-10 nM) at alpha-2B receptors. Using this definition, the human platelet appears to have only the alpha-2A subtype, while all the receptors in the neonatal rat lung are of the alpha-2B subtype. The rat brain has roughly equal amounts of alpha-2A and -2B receptors while in the rat submandibular gland, about 85% of the receptors are alpha-2A. The ability to pharmacologically define putative alpha-2 adrenergic receptor subtypes should promote the development of additional subtype selective drugs which will increase our understanding of adrenergic pharmacology and may provide new therapeutic approaches.

Animals↗
PubMed1993

Renal alpha-adrenergic receptors and genetic hypertension.

The hypothesis has been proposed that an increase in the number of renal alpha-adrenergic receptors may contribute to the pathogenesis of genetic hypertension. Herein we review recent findings regarding expression of renal alpha 1 (alpha 1a, alpha 1b)- and alpha 2 (alpha 2a, alpha 2b)-adrenergic subtypes and we provide an updated revision of the above-stated hypothesis. Enhancement in receptor number or in post-receptor components responsible for alpha 1- and alpha 2-adrenergic-mediated sodium reabsorption in proximal tubule may contribute to sodium retention and an elevation in blood pressure. Perhaps such changes contribute to the increase in blood pressure in genetically determined hypertension in humans, although direct tests of this notion have not yet been performed.

Animals↗
PubMed1997

Inhibition of milk ejection in cows by oxytocin receptor blockade, alpha-adrenergic receptor stimulation and in unfamiliar surroundings.

Inhibition of milk ejection in cows by oxytocin receptor blockade (Atosiban) and alpha-adrenergic receptor stimulation (phenylephrine) prior to prestimulation was compared with inhibition of milk ejection in unfamiliar surroundings. In addition, Atosiban and phenylephrine were administered after a 1 min prestimulation or 1 min after the start of milking. Oxytocin concentrations increased during milking in all treatments. The spontaneously removed milk fraction (before oxytocin was injected) was similar for Atosiban and phenylephrine treatments and in unfamiliar surroundings, but lower than in controls. Peak flow rates were similar in all treatments, but reduced as compared with controls when phenylephrine and Atosiban were administered before prestimulation. Peripheral (Atosiban, phenylephrine) and central (unfamiliar surroundings) inhibition of milk ejection reduced the amount of available milk similarity. Drug treatments resulted in similar peak flow rates; however, teats were contracted after phenylephrine administration but not after Atosiban. The inhibition induced by Atosiban could be abolished by oxytocin injection, but not induced by phenylephrine, which was antagonized by alpha-adrenergic receptor blockade. These results indicate that inhibition of milk ejection through activation of alpha-adrenergic receptors is based on blockade of milk flow into the cistern, but not through the teats.

Animals↗
PubMed2001

Hypoxia alters the sensitivity of the L-type Ca(2+) channel to alpha-adrenergic receptor stimulation in the presence of beta-adrenergic receptor stimulation.

The effects of alpha-adrenergic receptor (alpha-AR) stimulation alone and the effects in the presence of beta-adrenergic receptor (beta-AR) stimulation were examined on L-type Ca(2+) currents (I(Ca-L)) in the absence and presence of hypoxia. The alpha-AR agonist methoxamine either had no effect or had a slight inhibitory effect on basal I(Ca-L) in the absence and presence of hypoxia. Hypoxia significantly decreased the K(0.5) for activation of I(Ca-L) by norepinephrine from 79.8+/-6.6 to 13.3+/-0.7 nmol/L. To determine whether hypoxia specifically altered the sensitivity of the channel to alpha-AR stimulation, cells were exposed to increasing concentrations of methoxamine in the presence of 100 nmol/L isoproterenol (Iso). In the absence of hypoxia, methoxamine inhibited the Iso-activated I(Ca-L) in a concentration-dependent manner with an EC(50) of 86.9+/-9.9 micromol/L. However, in the presence of hypoxia, the EC(50) for inhibition of I(Ca-L) by methoxamine was significantly increased to 266.7+/-10.8 micromol/L. Methoxamine had little effect on I(Ca-L) activated by forskolin or histamine in the absence or presence of hypoxia. In addition, inhibition of protein kinase C by bisindolylmaleimide 1 or protein kinase C beta peptide inhibitor had no effect on the methoxamine-induced antagonism of I(Ca-L) in the absence or presence of hypoxia. The tyrosine kinase inhibitor genistein attenuated the methoxamine response in nonhypoxic cells only. However, during hypoxia it was attenuated with the phospholipase A(2) inhibitors mepacrine and indomethacin. These findings represent a novel regulation of the L-type Ca(2+) channel by the phospholipase A(2) pathway and illustrate the complexity of regulation of the channel under hypoxic conditions.

Adrenergic alpha-Agonists↗
PubMed1989

Pharmacological identification of the alpha-adrenergic receptor type which inhibits the beta-adrenergic activated adenylate cyclase system in cultured astrocytes.

The adrenergic agonist norepinephrine can exert its influence on cell function by activating both alpha- and beta-adrenergic receptors. In astrocytes, the alpha-adrenergic receptor activity of norepinephrine is known to inhibit the cyclic AMP response elicited by its action at beta-adrenergic receptors. Pharmacological studies were conducted to identify the subtype of alpha-adrenergic receptor which mediates this inhibitory action. The alpha 2-adrenergic antagonist yohimbine potentiated the cyclic AMP response elicited by norepinephrine, whereas the alpha 1-adrenergic antagonist prazosin did not affect the response. The alpha 2-adrenergic agonist clonidine inhibited the cyclic AMP response elicited by the beta-adrenergic agonist isoproterenol and this inhibition could be blocked by yohimbine but not by prazosin. In contrast, the alpha 1-adrenergic agonist phenylephrine did not inhibit the cyclic AMP response to isoproterenol. These studies indicate that the inhibitory action of norepinephrine is mediated by its action at alpha 2-adrenergic receptors.

Adenylyl Cyclases↗
PubMed1980

Adrenergic alpha receptors outnumber beta receptors in human penile corpus cavernosum.

Using specific adrenergic receptor binding assays, we characterized both alpha and beta adrenergic receptors in human penile corpus cavernosum tissue. The density of alpha adrenergic receptors in corporal tissue was found to be almost ten times greater than the density of beta adrenergic receptors. Our results are compatible with studies that suggest an important role for adrenergic innervation in penile erection.

Humans↗
PubMed1999

Cross-talk between alpha(1B)-adrenergic receptor (alpha(1B)AR) and interleukin-6 (IL-6) signaling pathways. Activation of alpha(1b)AR inhibits il-6-activated STAT3 in hepatic cells by a p42/44 mitogen-activated protein kinase-dependent mechanism.

Treatment of primary rat hepatocytes or tranfected HepG2 cells with the alpha(1B)-adrenergic receptor (alpha(1B)AR) agonist phenylephrine (PE) significantly inhibited interleukin 6 (IL-6)-induced STAT3 binding, tyrosine phosphorylation, and IL-6-induced serum amyloid A mRNA expression. Western analyses and in vitro kinase assays indicate that this inhibition is not due to either down-regulation of STAT3 protein expression nor inactivation of upstream-located JAK1 and JAK2. Blocking the new RNA and protein syntheses antagonized the inhibitory effect of PE on IL-6-activated STAT3, suggesting synthesis of an inhibitory factor(s) is involved. The inhibitory effect of PE on IL-6 activation of STAT3 was also abolished by the tyrosine phosphatase inhibitor sodium vanadate, indicating involvement of protein tyrosine phosphatases. Furthermore, preincubation of the cells with the specific MEK1 inhibitor PD98059 or a dominant negative MEK1 reversed the inhibitory effect of PE, and expression of constitutively activated MEK1 alone abolished IL-6-activated STAT3. Taken together, these data indicate that PE inhibits IL-6 activation of STAT3 in hepatic cells by a p42/44 mitogen-activated protein kinase-dependent mechanism, and tyrosine phosphatases are involved. This inhibitory cross-talk between the alpha(1B)AR and IL-6 signaling pathways implicates the alpha(1B)AR involvement in regulating the IL-6-mediated inflammatory responses.

Animals↗
PubMed1996

Transcriptional regulation of alpha(1b) adrenergic receptors (alpha(1b)AR) by nuclear factor 1 (NF1): a decline in the concentration of NF1 correlates with the downregulation of alpha(1b)AR gene expression in regenerating liver.

The 5' upstream region from --490 to --540 (footprint II) within the dominant P2 promoter of the rat alpha(1b) adrenergic receptor (alpha(1b)AR) gene is recognized by a sequence-specific DNA-binding protein (B. Gao, M. S. Spector, and G. Kunos, J. Biol. Chem. 270:5614-5619, 1995). This protein, detectable in Southwestern (DNA-protein) blots of crude nuclear extracts as 32- and 34-kDa bands, has been purified 6,000-fold from rat livers by DEAE-Sepharose, heparin-Sepharose, and DNA affinity chromatography. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and UV cross-linking of the purified protein indicated the same molecular mass as that in crude extracts. Methylation interference analysis revealed strong contact with a TTGGCT hexamer and weak contact with a TGGCGT hexamer in the 3' and 5' portions of footprint II, respectively. Nucleotide substitutions within these hexamers significantly reduced protein binding to footprint II and the promoter activity of P2 in Hep3B cells. The purified protein also bound to the nuclear factor 1 (NF1)/CTF consensus sequence, albeit with lower affinity. Gel mobility supershift and Western blotting (immunoblotting) analyses using an antibody against the NF1/CTF protein identified the purified 32- and 34-kDa polypeptides as NF1 or a related protein. Cotransfection into Hep3B cells or primary rat hepatocytes of cDNAs of the NF1-like proteins NF1/L, NF1/X, and NF1/Redl resulted in a three- to fivefold increase in transcription directed by wild-type P2 but not by the mutated P2. Partial hepatectomy markedly decreased the levels of NF1 in the remnant liver and its binding to P2, which paralleled declines in the rate of transcription of the alpha(1b)AR gene and in the steady-state levels of its mRNA. These observations indicate that NF1 activates transcription of the rat alpha(1b)AR gene via interacting with its P2 promoter and that a decline in the expression of NF1 is one of the mechanisms responsible for the reduced expression of the alpha(1b)AR gene during liver regeneration.

Animals↗
PubMed2004

Role of alpha-adrenergic receptors in the effect of the beta-adrenergic receptor ligands, CGP 12177, bupranolol, and SR 59230A, on the contraction of rat intrapulmonary artery.

This study investigates the effect of the aryloxypropanolamines 4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one (CGP 12177), bupranolol, and 3-(2-ethylphenoxy)-1[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol oxalate (SR 59230A) [commonly used as beta(3)- and/or atypical beta-adrenergic receptors (beta-AR) ligands] on the contractile function of rat intralobar pulmonary artery. Affinities of beta-AR ligands for alpha(1)-adrenergic receptors (alpha(1)-AR) were also evaluated using [(3)H]prazosin binding competition experiments performed in rat cortical membranes. In intralobar pulmonary artery, CGP 12177 did not modify the basal tone, but antagonized the contraction induced by the alpha(1)-AR agonist phenylephrine (PHE). In arteries precontracted with PHE, CGP 12177 elicited relaxation, whereas in those precontracted with prostaglandin F(2alpha) (PGF(2alpha)), it further enhanced contraction. CGP 12177 induced an increase in intracellular calcium concentration in pressurized arteries loaded with Fura PE-3 and precontracted with PGF(2alpha). In PGF(2alpha) precontracted arteries, phentolamine (an alpha-AR antagonist) and phenoxybenzamine (an irreversible alpha-AR antagonist) antagonized the contractile responses to PHE and CGP 12177. Both responses were also decreased by bupranolol and SR 59230A. Specific [(3)H]prazosin binding was displaced by CGP 12177, bupranolol, and SR 59230A with pK(i) values of 5.2, 5.7, and 6.6, respectively. In contrast, (+/-)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy]acetic acid sodium (BRL 37344) and disodium 5-[(2R)-2-([(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino)propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL 316243) (nonaryloxypropanolamines beta(3)-AR agonists) displayed very low affinity for [(3)H]prazosin binding sites (pK(i) values below 4). These data suggest that CGP 12177 exhibits partial agonist properties for alpha(1)-AR in rat pulmonary artery. They also show that bupranolol and SR 59230A exert an alpha(1)-AR antagonist effect. As a consequence, these aryloxypropanolamine compounds should be used with caution when investigating the role of beta(3)- and atypical beta-AR in the regulation of vascular tone.

Adrenergic alpha-Antagonists↗
PubMed1997

Longitudinal study of beta- and alpha-adrenergic receptor properties during human pregnancy.

OBJECTIVE: Our goal was to ascertain whether alterations in beta- and alpha-adrenergic receptor number and function (cyclic adenosine monophosphate production) occur during and after pregnancy. Because the actions of beta- and alpha2-adrenergic receptors tend to oppose each other, we hypothesized that there might be progressive, possibly reciprocal changes in these receptors during and after pregnancy. STUDY DESIGN: Blood was obtained from 21 women at 10, 20, 30, and 37 weeks of pregnancy and 3 to 4 months post partum. Lymphocyte beta- and platelet alpha2-adrenergic receptor number and affinity were quantified by radioligand binding studies, and receptor function was assessed by cyclic adenosine monophosphate generation assays. RESULTS: Although there were suggestions of progressive alterations in some of the variables studied, beta- and alpha2-adrenergic receptor number, affinity, and function did not manifest any statistically significant changes. CONCLUSION: Pregnancy did not produce marked alterations in beta-adrenergic receptor or alpha2-adrenergic receptor properties.

Adult↗
PubMed2000

Newly synthesized dopamine in the nucleus accumbens is regulated by beta-adrenergic, but not alpha-adrenergic, receptors.

Previous microdialysis studies have led to the hypothesis that activation of mesolimbic alpha-adrenoceptors inhibits the release of mesolimbic dopamine from alpha-methyl-p-tyrosine-resistant, reserpine-sensitive pools, and that activation of mesolimbic beta-adrenoceptors stimulates the release of mesolimbic dopamine from alpha-methyl-p-tyrosine-sensitive, reserpine-resistant pools. In the present study we analysed the ability of mesolimbic alpha- and beta-adrenoceptors to modulate the release of dopamine from alpha-methyl-p-tyrosine-sensitive pools in the nucleus accumbens of high and low responders to novelty. Under non-challenged conditions, alpha-methyl-p-tyrosine (10(-4)M, 40 min) produced a decrease in dopamine release that did not differ between high and low responders to novelty. The continuous infusion of 10(-6)M isoproterenol (beta-adrenoceptor agonist) diminished the alpha-methyl-p-tyrosine-induced decrease in dopamine, whereas the continuous infusion of 10(-5)M phenylephrine (alpha-adrenoceptor agonist) remained ineffective. It is concluded that the release of mesolimbic dopamine from alpha-methyl-p-tyrosine-sensitive, reserpine-resistant pools is under excitatory control of beta-adrenergic, but not alpha-adrenergic, receptors in both high and low responders to novelty. In general, this study implies that mesolimbic dopamine that is derived from different pools is regulated via different noradrenergic receptors.

Animals↗
PubMed1981

Increased alpha-adrenergic receptors in ischemic cat myocardium. A potential mediator of electrophysiological derangements.

We have recently demonstrated enhanced alpha-adrenergic responsiveness assessed electrophysiologically in ischemic and reperfused myocardium. This study was performed to determine whether ischemia alters alpha 1-adrenergic receptor number (Bmax) of affinity (KD) based on [3H]prazosin binding. Within 30 min after occlusion, Bmax increased in ischemic regions to 207% of control to 27 +/- 2 fmol/mg protein, with the increase persisting (+ 141% of control) during early reperfusion (2 min), before returning to control base-line values (13 +/- 1.6) after 15 min of reperfusion. KD was not altered at any interval studied. Beta receptor number of ([3H]dihydroalprenolol) and Na+-K+ ATPase activity were comparable in control compared to ischemic myocardium although beta-receptor Bmax and KD in both regions decreased during early reperfusion. Thus, the enhanced alpha-adrenergic responsivity previously recognized with ischemia and reperfusion is correlated with an increase in alpha 1-adrenergic receptors.

Animals↗
PubMed2001

Attention-deficit hyperactivity disorder and the adrenergic receptors alpha 1C and alpha 2C.

The adrenergic system has been hypothesized to be involved in the etiology of attention-deficit hyperactivity disorder (ADHD) based on pharmacological interventions and animal models. Noradrenergic neurons are implicated in the modulation of vigilance, improvement of visual attention, initiation of adaptive response, learning and memory. In this study we tested the genes for two adrenergic receptors, alpha 1C (ADRA1C) located on chromosome 8p11.2, and alpha 2C (ADRA2C) located on chromosome 4p16, as genetic susceptibility factors in ADHD. For the adrenergic receptor alpha 1C we used a C to T polymorphism that results in a change of Cys to Arg at codon 492 for the linkage study. For the adrenergic receptor alpha 2C gene we examined a dinucleotide repeat polymorphism located approximately 6 kb from the gene. We examined these polymorphisms in a sample of 103 families ascertained through an ADHD proband. Using the transmission disequilibrium test, we did not observe biased transmission of any of the alleles of these polymorphisms. We conclude that the alleles at the polymorphisms tested in these two genes are not linked to the ADHD phenotype in this sample of families.

Attention Deficit Disorder with Hyperactivity↗