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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

alpha2-Adrenergic receptors (ARs) play a key role in regulating neurotransmitter release in the central and peripheral sympathetic nervous systems. To date, three subtypes of alpha2-ARs have been cloned (alpha2A, alpha2B, and alpha2C). Here we describe the physiological consequences of disrupting the gene for the alpha2A-AR. Mice lacking functional alpha2A subtypes were compared with wild-type (WT) mice, with animals lacking the alpha2B or alpha2C subtypes, and with mice carrying a point mutation in the alpha2A-AR gene (alpha2AD79N). Deletion of the alpha2A subtype led to an increase in sympathetic activity with resting tachycardia (knockout, 581 +/- 21 min-1; WT, 395 +/- 21 min-1), depletion of cardiac tissue norepinephrine concentration (knockout, 676 +/- 31 pg/mg protein; WT, 1178 +/- 98 pg/mg protein), and down-regulation of cardiac beta-ARs (Bmax: knockout, 23 +/- 1 fmol/mg protein; WT, 31 +/- 2 fmol/mg protein). The hypotensive effect of alpha2 agonists was completely absent in alpha2A-deficient mice. Presynaptic alpha2-AR function was tested in two isolated vas deferens preparations. The nonsubtype-selective alpha2 agonist dexmedetomidine completely blocked the contractile response to electrical stimulation in vas deferens from alpha2B-AR knockout, alpha2C-AR knockout, alpha2AD79N mutant, and WT mice. The maximal inhibition of vas deferens contraction by the alpha2 agonist in alpha2A-AR knockout mice was only 42 +/- 9%. [3H]Norepinephrine release studies performed in vas deferens confirmed these findings. The results indicate that the alpha2A-AR is a major presynaptic receptor subtype regulating norepinephrine release from sympathetic nerves; however, the residual alpha2-mediated effect in the alpha2A-AR knockout mice suggests that a second alpha2 subtype (alpha2B or alpha2C) also functions as a presynaptic autoreceptor to inhibit transmitter release.
Mol Pharmacol 1999 Jul
PMID:Abnormal regulation of the sympathetic nervous system in alpha2A-adrenergic receptor knockout mice. 1038 96

The early growth response gene Egr-1 is a nuclear transcription factor known to serve as an intermediary in a broad range of signal transduction processes. Recent studies have assigned Egr-1 a new role as an amplifier of gene expression. Egr-1 mRNA is expressed in the myocardium and is rapidly induced in response to hypertrophic stimuli. However, induction of the Egr-1 protein has not yet been demonstrated in the myocardium; on the other hand, in skeletal muscle cells we have shown translational regulation of Egr-1. To further investigate the role of Egr-1 in the regulatory mechanisms of a variety of signal transduction processes we have therefore asked whether bona fide hypertrophic stimuli induce Egr-1 protein subsequently to its mRNA in neonatal rat cardiomyocytes or whether translational block occurs. In confocal laser studies the Egr-1 protein was nuclearly localized. Norepinephrine (NE, 2 microM), angiotensin II (AII, 0.1 microM), and endothelin 1 (E1, 0.1 microM) each induced the Egr-1 mRNA 6-8 fold and the Egr-1 protein 3-5 fold (n = 3, p < 0.01). Therefore, in contrast to skeletal muscle cells, these stimuli increased Egr-1 mRNA and protein levels. These results point further to the role of Egr-1 as a possible amplifier of signal transduction in the myocardium.
Mol Cell Biochem 1999 May
PMID:Induction of Egr-1 mRNA and protein by endothelin 1, angiotensin II and norepinephrine in neonatal cardiac myocytes. 1039 64

The aim of the study was to use the isolated blood-perfused rat heart to: (i) determine whether brief intermittent rapid pacing and ventricular fibrillation are able to mimic preconditioning by ischemia and thereby protect the isolated blood-perfused heart against ischemia-induced injury and (ii) characterize the effects of these interventions on cardiac metabolism. To this end, isolated, blood-perfused (2.4 ml/min), paced (360 beats/min) rat hearts (n = 6/group), were aerobically perfused for 20 min. Hearts were then randomized to four groups: (i) a further 16 min aerobic perfusion (UC, untreated controls), (ii) ischemic preconditioning (IP, 3 min ischemia + 3 min reperfusion followed by 5 min ischemia + 5 min reperfusion), (iii) electrically induced ventricular fibrillation (VF, 3 min fibrillation + 3 min sinus rhythm followed by 5 min fibrillation + 5 min sinus rhythm) and (iv) rapid pacing at > or = 600 beats/min (RP, 3 min rapid pacing + 3 min normal heart rate followed by 5 min rapid pacing + 5 min normal heart rate). Hearts were then subjected to 35 min of zero-flow, global ischemia (37 degrees C) and 40 min reperfusion. In parallel studies, blood samples were collected during the first 3 min of treatment and plasma taken for the analysis of noradrenaline. The hearts were then immediately frozen and assayed for high energy phosphates and noradrenaline content. Time-to-50% contracture during ischemia was 13.2 +/- 0.8 min in controls; this was reduced to 6.3 +/- 1.1 min by IP but was unaffected by VF or RP (12.4 +/- 1.1 and 12.8 +/- 1.2 min respectively). Post-ischemic left ventricular developed pressure (LVDP) in untreated controls recovered to only 19.9 +/- 8.4% of its pre-ischemic value whereas with IP, VF and RP substantial and similar improvements were observed (60.3 +/- 7.4, 56.2 +/- 5.7 and 45.3 +/- 10.3%, respectively, P < 0.01). This protection was achieved without any significant depletion of high energy phosphates during VF or RP. Noradrenaline was essentially unchanged in controls and with RP, but VF caused a loss from tissue and a large elevation in the plasma. Our results suggest that both RP and VF are as effective as brief ischemia in protecting the heart against injury during ischemia and reperfusion. In contrast to IP, this protection can be achieved without the exacerbation of ischemic contracture and without inducing ischemia during the preconditioning period.
J Mol Cell Cardiol 1999 Nov
PMID:Cardioprotection: intermittent ventricular fibrillation and rapid pacing can induce preconditioning in the blood-perfused rat heart. 1059 Oct 23

Norepinephrine (NE) is thought to play a role in the stress response, and may be involved in stress-related psychopathological conditions such as depression or anxiety. Heterogeneity in individual responses to the same stressor suggest that a genetic susceptibility to the effects of stress may contribute to such pathology. To address possible mechanisms underlying this genetic aspect of the stress response, we examined acute stress-induced changes in mRNA expression for several components of the NE system in the locus coeruleus (LC) and adrenal medullae of stress-susceptible Wistar-Kyoto (WKY) rats and their parent Wistar (W) strain. Expression of tyrosine hydroxylase (TH), NE transporter (NET) and alpha(2A) receptor mRNA were measured in the LC by in situ hybridization 30 min and 2 h after the onset of 30 min restraint stress. Adrenal TH mRNA was measured by slot blots. No basal differences were observed for any measure, but in the LC, expression of TH mRNA increased by 40% in W rats at 30 min (n=8, p<0.05) and returned toward baseline by 2 h, while WKY rats showed only a non-significant 29% increase at 2 h. In contrast, adrenal TH mRNA expression increased in WKY rats at 2 h (n=3, p<0.05), with no significant change in W rats. NET and alpha(2A) mRNA were unaltered by restraint stress in both strains. Differences in the stress-reactivity of TH gene expression in the central and peripheral noradrenergic systems may be related to differences in behavioral coping strategies and autonomic responsivity to stress in these strains, and suggest that differences in noradrenergic reactivity may contribute to genetic susceptibility to stress-related pathology.
Brain Res Mol Brain Res 2000 Jan 10
PMID:Effects of acute restraint stress on tyrosine hydroxylase mRNA expression in locus coeruleus of Wistar and Wistar-Kyoto rats. 1064 82

During symbiotic nodule development, a variety of molecular signals of rhizobia and plant origin are likely to be involved in the control of the expression of specific genes in the legume Medicago sativa (alfalfa). Twenty-two new, nodule-associated Expressed Sequence Tags (ESTs, MsNod clones) as well as 16 clones for previously reported alfalfa nodulins were identified by cold-plaque screening. Protein homologs were found for 10 of the 22 MsNod-encoded polypeptides, revealing putative novel functions associated with this symbiosis. Expression of these MsNod genes was investigated in spontaneous nodules (generated in the absence of bacteria), in nodules induced by a Sinorhizobium meliloti wild-type strain and Eps- and Bac- mutant derivatives, as well as in roots inoculated with a Nod- mutant strain. This analysis enabled us to correlate plant gene expression with the different stages of nodule ontogeny and invasion. The effect of phytohormones on MsNod gene expression was analyzed in cytokinin- and auxin-treated alfalfa roots. Cytokinin induced the accumulation of seven MsNod transcripts, four of them were also regulated by the synthetic auxin 2,4-D (2,4-dichlorophenoxyacetic acid). Comparison of MsNod expression profiles in wild-type and transgenic M. truncatula roots overexpressing the early nodulin Enod40 suggested that one clone, the M. sativa L3 ribosomal protein homolog (MsNod377), is a putative component of an Enod40-dependent pathway acting during nodule development. These novel molecular markers may help in the investigation of gene networks and regulatory circuits controlling nodule organogenesis.
Mol Plant Microbe Interact 2000 Jan
PMID:Expression profiles of 22 novel molecular markers for organogenetic pathways acting in alfalfa nodule development. 1065 90

The effect of lysophosphatidic acid on the phosphorylation and function of alpha(1b)-adrenoceptors transfected into rat-1 fibroblasts was studied. This phospholipid mitogen increased in a concentration-dependent fashion (EC(50) approximately 50 nM) the phosphorylation of these adrenoceptors. Lysophosphatidic acid-induced alpha(1b)-adrenoceptor phosphorylation was relatively rapid (t(1/2) approximately 1 min), intense (2.5-fold), and sustained for at least 60 min. The effect of lysophosphatidic acid was blocked by pretreatment with pertussis toxin. The alpha(1b)-adrenoceptor phosphorylation induced by lysophosphatidic acid was not blocked by genistein, a tyrosine kinase inhibitor, but it was inhibited by inhibitors of protein kinase C (bisindolylmaleimide I, staurosporine, and Ro 31-8220) and phosphoinositide 3-kinase (wortmannin and LY 294002). The ability of norepinephrine to increase cytosol calcium concentration was markedly decreased in cells previously challenged with lysophosphatidic acid. Norepinephrine-induced [(35)S]GTPgammaS binding in membrane preparations was used as an index of the functional coupling of the alpha(1b)-adrenoceptors and G proteins. Norepinephrine-stimulated [(35)S]GTPgammaS binding was markedly decreased in membranes from cells pretreated with lysophosphatidic acid. This effect of lysophosphatidic acid was blocked by pretreatment with wortmannin or staurosporine. Our data indicate that: 1) activation of lysophosphatidic acid receptors induce phosphorylation of alpha(1b)-adrenoceptors; 2) this effect is mediated through pertussis toxin-sensitive G proteins, phosphatidylinositol 3-kinase, and protein kinase C; and 3) the phosphorylation of alpha(1b)-adrenoceptors induced by the lipid mitogen is associated to adrenoceptor desensitization.
Mol Pharmacol 2000 May
PMID:Lysophosphatidic acid modulates alpha(1b)-adrenoceptor phosphorylation and function: roles of Gi and phosphoinositide 3-kinase. 1077 88

The effects of norepinephrine on ketogenesis in isolated hepatocytes have been reported as ranging from stimulation to inhibition. The present work was planned with the aim of clarifying these discrepancies. The experimental system was the once-through perfused liver from fasted and fed rats. Fatty acids with chain lengths varying from 8-18 were infused. The effects of norepinephrine depended on the metabolic state of the rat and on the nature of the fatty acid. Norepinephrine clearly inhibited ketogenesis from long-chain fatty acids (stearate > palmitate > oleate), but had little effect on ketogenesis from medium-chain fatty acids (octanoate and laureate). With palmitate the decrease in oxygen uptake was restricted to the substrate stimulated portion; with stearate, the decrease exceeded the substrate stimulated portion; with oleate, oxygen uptake was transiently inhibited. Withdrawal of Ca2+ attenuated the inhibitory effects. 14CO2 production from [1-14C]oleate was inhibited. Net uptake of the fatty acids was not affected by norepinephrine. In livers from fed rats, oxygen uptake and ketogenesis from stearate were only transiently inhibited. The conclusions are: (a) in the fasted state norepinephrine reduces ketogenesis and respiration by means of a Ca2+-dependent mechanism; (b) the degree of inhibition varies with the chain length and the degree of saturation of the fatty acids; (c) norepinephrine favours esterification of the activated long-chain fatty acids in detriment to oxidation; (d) in the fed state the stimulatory action of norepinephrine on glycogen catabolism induces conditions which are able to reverse inhibition of ketogenesis and oxygen uptake.
Mol Cell Biochem 2000 Feb
PMID:Effects of norepinephrine on the metabolism of fatty acids with different chain lengths in the perfused rat liver. 1082 18

Catecholamines modulate cardiac function at least in part through alpha(1)-adrenergic receptors linked to the activation of protein kinase C (PKC). This study examines the molecular forms of the alpha(1)-receptor and PKC that mediate norepinephrine's actions in cardiomyocytes; distinct approaches (activation-dependent down-regulation of PKC isoforms) and novel reagents (A61603, an alpha(1A/c)-receptor agonist) are used to resolve this issue which has been the focus of dispute in previous studies. Norepinephrine (NE) induces a rise in diacylglycerol levels which is sustained for 24 h and is associated with the translocation (at 5 min) and down-regulation (at 24 h) of PKC delta and PKC xi (but not PKC alpha). The selective targeting of the alpha(1)-adrenergic receptor to activate novel PKC isoforms is remarkable, given an 8-fold greater abundance of PKC alpha relative to PKC xi in this preparation. NE activates the extracellular signal-regulated protein kinase (ERK) subfamily of mitogen-activated protein kinases through a PKC delta/PKC xi -dependent pathway. WB-4101 (alpha(1A/c)- and alpha(1D)-receptor antagonist) and 5-methylurapidil (alpha(1A/c)-receptor antagonist) inhibit norepinephrine-dependent accumulation of inositol phosphate and diacylglycerol, down-regulation of PKC delta and PKC xi, and activation of ERK. Each of these responses is stimulated by A61603, but not attenuated by high concentrations of chloroethylclonidine (which irreversibly inactivates the alpha(1B)-, and to a lesser extent, the alpha(1D)-receptor) or BMY 7378 (selective alpha(1D)-receptor antagonist). A61603 also activates p38-MAPK and induces hypertrophy. These studies establish that NE's actions in cardiomyocytes can be attributed to the alpha(1A/c)-adrenergic receptor subtype and nPKC isoforms, thereby identifying specific targets for the development of pharmaceuticals to influence cardiac contractile function and/or growth responses.
J Mol Cell Cardiol 2000 Jul
PMID:The alpha(1)-adrenoceptor subtype- and protein kinase C isoform-dependence of Norepinephrine's actions in cardiomyocytes. 1086 Jul 63

The aim of this study was to establish whether epicardial transudates could be used to uncover small, but physiologically important changes in interstitial NE concentrations under normal and pathological conditions. Norepinephrine (NE) concentrations measured in epicardial transudate fluid were compared to NE levels in the coronary effluent in normal and pressure overload hypertrophied (POH) rat hearts. Hearts were isolated together with the stellate ganglion and perfused in the inverted position. Epicardial surface transudates, representative fluid of the interstitial myocardial compartment, and coronary effluents were collected for determination of NE levels in the presence and absence of stellate ganglion stimulation. The same protocol was repeated in the presence and absence of nisoxetine, a NE uptake blocker. NE concentrations in epicardial transudates were 16- and 19-fold higher than in the coronary effluent in both sham and POH groups, respectively. NE concentrations in the transudates but not in the coronary effluents were significantly higher (1.6-fold) in hearts with POH when compared to normal hearts. Likewise, nisoxetine (10(-5)m) increased (1.3-fold) NE concentrations in the transudates but not in the effluents of sham animals. As expected, stellate ganglion stimulation increased NE concentrations in both transudates and effluents in sham and POH hearts. In conclusion, determination of NE concentrations in epicardial transudates represents a simple, rapid and sensitive method to detect increases in adrenergic activity in normal and abnormal hearts.
J Mol Cell Cardiol 2000 Sep
PMID:Norepinephrine concentrations in the epicardial transudate reflect early changes in adrenergic activity in the isolated perfused heart. 1096 32

Norepinephrine (NE) causes hypertrophic growth of cardiac myocytes via stimulation of alpha1-adrenergic receptors (alpha1-AR). Reactive oxygen species (ROS) can act as signaling molecules for cell growth. Accordingly, we tested the hypothesis that ROS mediate alpha1-AR-stimulated hypertrophic growth in adult rat ventricular myocytes (ARVM). NE increased the level of intracellular ROS as assessed by lucigenin chemiluminescence or cytochrome c reduction, and this effect was prevented by the superoxide dismutase (SOD)-mimetic MnTMPyP. NE also caused the induction of MnSOD mRNA. alpha1-AR stimulation with NE (1 microM) in the presence of propranolol (2 microM) for 48-96 h caused a hypertrophic growth phenotype characterized by a 36+/-3% increase in 3H-leucine incorporation, a 49+/-14% increase in protein accumulation, a six-fold induction of atrial natriuretic peptide mRNA, actin filament reorganization, and the induction of MnSOD mRNA. These responses were all prevented by pretreatment with the alpha1-AR-selective antagonist prazosin (100 n M) or the SOD-mimetics MnTMPyP (50 microM) and Euk-8 (100 microM). MnTMPyP had no effect on alpha1-AR-stimulated 3H-inositol phosphate turnover or the hypertrophic phenotype caused by the protein kinase C activator phorbol-12-myristate-13-acetate. Thus, ROS play a critical role in mediating the hypertrophic growth response to alpha1-AR-stimulation in ARVM.
J Mol Cell Cardiol 2001 Jan
PMID:Reactive oxygen species mediate alpha-adrenergic receptor-stimulated hypertrophy in adult rat ventricular myocytes. 1113 29


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