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

The response of cytosolic phosphates ([ATP], [PCr], [Pi] and [ADP]) in rat hearts retrogradely perfused with different oxidizable substrates to increased workload induced by elevated coronary flow (CF) or by addition of inotropic agents has been investigated. Hearts were perfused with glucose (11 mM), pyruvate (5 mM), lactate (3 mM) or a combination of glucose (5.5 mM) and acetate (5 mM), octanoate (0.1 mM) or beta-hydroxybutyrate (5 mM). The initial [ATP]/[ADP] ratio was highest in pyruvate and lactate perfused hearts. Increasing the coronary flow 1.7-fold (from c. 56 to 96 ml/min x g dry wt) resulted in an increase in pressure-rate product (PRP) by 36-52% without significant changes in cytosolic phosphates. Dichloroacetate (1 mM), ruthenium red (2.5 micrograms/ml), or pre-treatment with theophylline (1 mM, 30 min) had no effect either functional or metabolic response to elevated CF in glucose-perfused hearts. Isoproterenol (Iso, 0.1 microM) infusion at maximal coronary flows lead to further elevation of PRP value by 36-88% and the ratio of the maximal rate of relaxation to LV developed pressure ((-dP/dt)m/LVDP) increased two-fold. Simultaneously, [PCr] decreased by 18-30%, [Pi] increased two-fold and ADP increased by 20-90% resulting in reduction of [ATP]/[ADP] by half and ATP affinity (A(ATP) = -delta G(ATP)) by 2.4-3.8 kJ/mol. In hearts perfused with acetate, octanoate and hydroxybutyrate in the presence of glucose, Iso addition resulted in intracellular pH decrease by 0.03-0.07 U and increase in lactate extrusion 1.5-2 times. In hearts perfused with glucose alone, decrease in PRP induced by perfusate Ca2+ reduction was associated with increase in PCr and decrease in Pi levels. These data show that coordinated regulation of energy supply and demand exerted by coronary flow/perfusion pressure does not depend on the availability of reducing equivalents but is rather controlled by oxygen supply and stretch-activated factors.
J Mol Cell Cardiol 1993 Oct
PMID:Regulation of cardiac energy turnover by coronary flow: a 31P-NMR study. 750 38

Effects of various receptor agonists on cytoplasmic Ca2+ concentration ([Ca2+]i) were examined in fura-2-loaded Mardin-Darby canine kidney (MDCK) monolayer cells. Carbachol (100 microM) increased [Ca2+]i which slightly declined to a sustained increase in [Ca2+]i. On the other hand, [Ca2+]i elevated by 100 nM bradykinin (BK) declined to a resting level of [Ca2+]i even in the presence of BK. After washout of BK, the subsequent addition of a higher concentration of BK (1 microM) caused a smaller increase in [Ca2+]i than that induced by 100 nM BK. Isoproterenol (100 microM) did not increase [Ca2+]i by itself but caused an transient increase in [Ca2+]i in the presence of 1 mM isobutyl-methylxanthine (IBMX). Prostaglandin E1 (1 microM) resulted in a slight increase in [Ca2+]i which was potentiatedin the presence of 1 mM IBMX. The microsomal Ca(2+)-ATPase inhibitor thapsigargin (100 nM) caused a sustained increase in [Ca2+]i. These results suggest that MDCK cells have multiple Ca2+ signaling pathways which may regulate epithelial cell functions.
Res Commun Mol Pathol Pharmacol 1994 Nov
PMID:Multiple calcium signaling pathways in Mardin-Darby canine kidney cells. 753 28

Although it is well known that myocardial ischemia induces the depletion of myocardial ATP and sustained myocardial dysfunction, the mechanisms causing impaired myocardial function have not been elucidated completely. To clarify the relationship between ATP depletion and myocardial contractility, we investigated the influence of myocardial ATP depletion on spontaneous beating in cultured rat ventricular myocytes. Furthermore, because catecholamines have been used to improve myocardial contraction in the ischemic heart, we attempted to determine whether the ATP depletion per se alters the contractile responses to alpha 1- and beta-adrenoceptor stimulation. After 24 hr of culture in the presence of a metabolic inhibitor, 2-deoxyglucose (2DG, 5mM), myocardial contractility decreased to 19% of the vehicle level, and returned to normal after the removal of 2DG. The beating rate did not show any alterations in the vehicle, in the presence of 2DG (2DG [+/+]) or after the removal of 2DG (2DG [+/-]). Norepinephrine (NE) caused significant decreases in beating rate and increases in contractility in all groups. Isoproterenol (ISP) caused significant increases in beating rate and contractility in all groups. In the 2DG (+/+) group, the contractility was significantly lower as compared to other groups during NE or ISP stimulation. However, the percent change of contractility was similar to those of other groups after NE or ISP stimulation in the 2DG (+/+) group. These results suggest that decreased myocardial ATP causes the decreased contractility and does not affect the alpha 1- or beta-adrenoceptor-mediated responses.
Res Commun Mol Pathol Pharmacol 1995 Jul
PMID:Effects of 2-deoxyglucose, a metabolic inhibitor, on spontaneous contraction and adrenoceptor responsiveness in cultured rat ventricular myocytes. 758 56

Incubation of rat C6 glioma cells with beta-adrenergic receptor (beta AR) agonist or with agents that increase cAMP levels results in down-regulation of the beta 2AR, as measured by the loss of radioligand binding sites. In the present study, the role of beta 2AR mRNA expression and stability in the down-regulation of beta 2AR sites in C6 cells was examined. Isoproterenol or forskolin treatment decreased beta 2AR mRNA levels in a time-dependent manner, with maximal loss of approximately 50% being observed after 2 hr. Pretreatment of the cells with a potent protein synthesis inhibitor, Pseudomonas exotoxin A, completely blocked isoproterenol- and forskolin-mediated down-regulation of beta 2AR mRNA. Exposure to agonist did not significantly influence the half-life of beta 2AR mRNA, which was approximately 60 min. In contrast, isoproterenol treatment for 2 hr significantly decreased the rate of beta 2AR gene transcription, as determined by nuclear run-on analysis. Based on these results, we propose that agonist regulation of beta 2AR mRNA in C6 cells is mediated by activation of the cAMP system and occurs at the level of beta 2AR gene transcription, not mRNA stability. In addition, the observed requirement for protein synthesis indicates that down-regulation of beta 2AR mRNA may be mediated by expression of a repressor of beta 2AR gene transcription.
Mol Pharmacol 1995 Aug
PMID:Regulation of beta 2-adrenergic receptor mRNA and gene transcription in rat C6 glioma cells: effects of agonist, forskolin, and protein synthesis inhibition. 765 53

Opioids are known to have an inhibitory effect on the secretion of luteinizing hormone releasing hormone (LHRH) when administered to whole animals in vivo or when applied to hypothalamic fragments in vitro. Whether opioids have this effect by acting directly on the LHRH secreting neurons or require the mediation of an interneuron is controversial. To examine this question, a clonal cell line derived from a hypothalamic neuron (GT1-7) was perfused and fractions collected every 6 min. Morphine treatment had no effect on basal secretion of LHRH, nor on the spontaneous, pulsatile release of LHRH. Isoproterenol, dopamine, and serotonin all produced significant increments in LHRH secretion. Pretreatment of GT1-7 cells for 2 h with morphine, suppressed the LHRH response to isoproterenol and dopamine but had no apparent effect on serotonin-induced LHRH release. These data indicate that morphine has a direct effect on GT1-7 cells that alters their responsiveness to some, but not all, LHRH secretagogues. These results suggest that, in vivo, the inhibitory effects that opioids have on LHRH release may not require an interneuron.
Mol Cell Neurosci 1994 Dec
PMID:Opioid inhibition of adrenergic and dopaminergic but not serotonergic stimulation of luteinizing hormone releasing hormone release from immortalized hypothalamic neurons. 770 39

We functionally expressed alpha 2-adrenergic, beta 2-adrenergic, and delta-opioid receptors in Xenopus laevis oocytes. We detected receptor function as changes in currents carried by adenosine 3',5'-cyclic monophosphate (cAMP)-regulated chloride channels provided by the cystic fibrosis transmembrane conductance regulator (CFTR) and recorded by two-electrode voltage clamp. Co-application of forskolin and isobutylmethylxanthine (IBMX) or IBMX alone produced currents with a reversal potential indicative of chloride ions only in oocytes previously injected with mRNA encoding CFTR. Isoproterenol produced concentration-dependent responses in oocytes injected with mRNA encoding beta 2-adrenergic receptors and CFTR, and co-administration of propranolol antagonized these responses. Similarly, the alpha 2-adrenergic agonist UK14304 increased IBMX-induced currents only in oocytes injected with mRNA encoding alpha 2-adrenergic receptors and CFTR, and idazoxan antagonized these enhancements. The delta-opioid agonist DADLE produced concentration-related, naloxone-reversible increases in IBMX- and forskolin-induced currents only in oocytes injected with mRNA encoding delta-opioid receptors and CFTR. In oocytes co-injected with alpha 2, beta 2, and CFTR mRNAs, isobolographic analysis revealed an additive interaction between alpha 2- and beta 2-adrenergic receptors. These studies establish the oocyte as a cell system for studying the interactions among cAMP-modulating G protein-coupled receptors and provide another example of alternative coupling of alpha 2-adrenergic and delta-opioid receptors to G proteins, possibly Gs proteins, other than Gi proteins.
Brain Res Mol Brain Res 1995 Jan
PMID:Functional expression of adrenergic and opioid receptors in Xenopus oocytes: interaction between alpha 2- and beta 2-adrenergic receptors. 770 80

The short-term effects of two different secretagogues on the water contained in the mouse submandibular gland were studied using the thermal analysis as investigation method. Isoproterenol induced a retention while pilocarpine promoted a release of weakly and strongly bound water. In addition, submandibular glands of subjects administered with isoproterenol were characterized by a thermal behaviour different in males and females above all as concerns the time of reaction to the secretagogue; the reaction delay observed in females was correlated with the effects of this pharmacological substance on the convoluted granular tubules that are responsible for the sexual dimorphism in mice.
Cell Mol Biol (Noisy-le-grand) 1994 Sep
PMID:Quantitative and qualitative fluctuation of water in the mouse submandibular gland under secretagogue effect. 781 86

Isoproterenol is a beta adrenergic agonist whose effects have been attributed to the generation of cAMP. Previous studies have shown that it inhibits glucose transport in adipocytes without changing the number of insulin-responsive glucose transporters (GLUT4) on the cell surface. However, we have shown previously that cAMP stimulates translocation of GLUT4 to the cell surface in adipocytes (Kelada et al. J Biol Chem 267, 7021-7025, 1992). We therefore further investigated the mechanisms involved in isoproterenol regulation of glucose transport. Consistent with the effects of dibutyryl cAMP, we found that a low concentration of isoproterenol (10 nM) stimulated glucose transport and the translocation of GLUT4 from the low density microsomal fraction to the plasma membrane. By contrast, a higher concentration of isoproterenol (1 microM) did not stimulate transport or GLUT4 translocation and furthermore inhibited dibutyryl cAMP-stimulated GLUT4 translocation. This inhibitory effect was specific for cAMP since isoproterenol had no effect on insulin-stimulated GLUT4 translocation. We conclude that isoproterenol has a biphasic effect on glucose transport, mediated by acute translocation of GLUT4 at low concentrations and by inhibition of intrinsic activity at high concentration, both of which may be explained by effects of cAMP. It has a further cAMP-independent effect at high concentration to inhibit cAMP-mediated translocation of GLUT4.
Mol Cell Biochem 1994 Dec 07
PMID:Isoproterenol inhibits cyclic AMP-mediated but not insulin-mediated translocation of the GLUT4 glucose transporter isoform. 787 6

Previous animal experiments indicated that the effects of catecholamines on myocardial function and subcellular systems vary considerably depending on the species and type of myocardium investigated. In the present study, we used isometric force and heat measurements to investigate the influence of isoproterenol on energetics of excitation-contraction coupling and contractile proteins in isolated nonfailing human myocardium. Isoproterenol, in an average concentration of 0.8 +/- 0.3 microM, resulted in a significant increase in peak twitch tension, maximum rate of tension rise and maximum rate of tension fall by 46% (P < 0.025), 126% (P < 0.001) and 137% (P < 0.005), respectively (37 degrees C, 60 beat/min). The amount and rate of excitation-contraction coupling-related heat evolution (tension-independent heat) increased by 116% (P < 0.03) and 176% (P < 0.02), respectively. Furthermore, the relationship of tension-independent heat to isometric tension or tension-time integral increased by 47% (P < 0.05) and 91% (P < 0.01), respectively. That is, the energy used in calcium cycling increased by a greater proportion than did mechanical output. Isoproterenol increased the rate of the acto-myosin crossbridge high-energy phosphate hydrolysis (tension-dependent heat rate) by 61% (P < 0.006) and decreased the force-time integral (consistent with decrease in the attachment time) of the individual crossbridge cycle by 21% (P < 0.025). Decreased crossbridge force-time integral with isoproterenol indicates decreased economy of isometric force production at the level of the contractile proteins. Increased energy turnover of excitation-contraction coupling processes and reduced force-time integral generation by the individual crossbridge cycle resulted in increased myocardial energy turnover as indicated by a 41% increase in the ratio of total activity related heat per tension-time integral (P < 0.02). The efficiency of the metabolic recovery process as assessed by the ratio of initial heat to total activity related heat, was similar with and without isoproterenol (0.52 +/- 0.05 v 0.49 +/- 0.03; P > 0.05). Thus, isoproterenol significantly influences excitation-contraction coupling processes and crossbridge cycling, thereby increasing myocardial energy turnover per unit of isometric force production in the human myocardium.
J Mol Cell Cardiol 1994 Nov
PMID:Influence of isoproterenol on contractile protein function, excitation-contraction coupling, and energy turnover of isolated nonfailing human myocardium. 789 70

During the course of equilibrium competition binding assays with intact cells, agonists induce conversion of beta-adrenergic receptors (BARs) from a native form with high affinity for agonists to a form with a markedly lower apparent affinity. The roles of receptor internalization, receptor-Gs coupling, and receptor phosphorylation in this agonist-induced conversion to the low affinity form were investigated. Agonist and antagonist competition for [125I]iodopindolol binding to intact cells was measured in mouse L cells expressing wild-type BARs (C+I+), mutated BARs that do not couple to Gs but do internalize (C-I+), and mutated BARs that do not couple to Gs and do not internalize (C-I-). For C+I+ and C-I+ cells, most of the receptors exhibited apparent affinities for the agonist isoproterenol that were 500-900-fold lower in equilibrium assays with intact cells than in short-time assays with intact cells or in equilibrium assays with isolated membranes, similar to previous results with cells expressing native BARs. The extent of conversion to this lower affinity form for C-I- cells was markedly decreased. Binding properties for the antagonist metoprolol were similar for all three BARs in both short-time and equilibrium assays. Isoproterenol competition in short-time and equilibrium assays also was compared in Chinese hamster fibroblasts expressing wild-type BARs, mutated BARs that lack BAR kinase sites, mutated BARs that lack cAMP-dependent protein kinase sites, and mutated BARs that lack both types of phosphorylation sites. All three BAR phosphorylation mutants showed only small but significant decreases, relative to the wild-type BAR, in the extent of conversion to the low affinity form. These results provide additional evidence that receptor internalization is the major determinant for the conversion of intact cell BARs to the low affinity form. Receptor phosphorylation may play a minor role in conversion to the low affinity form, whereas receptor coupling to Gs is apparently not required.
Mol Pharmacol 1994 Feb
PMID:Intact cell binding properties of cells expressing altered beta-adrenergic receptors. 790 55


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