The Experts below are selected from a list of 129 Experts worldwide ranked by ideXlab platform
Luigi A. Venetucci - One of the best experts on this subject based on the ideXlab platform.
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In the RyR2R4496C mouse model of CPVT, β-Adrenergic stimulation induces ca waves by increasing SR Ca content and not by decreasing the threshold for Ca Waves
Circulation Research, 2010Co-Authors: Takeshi Kashimura, Sarah J. Briston, Carlo Napolitano, Andrew W. Trafford, David A. Eisner, Silvia G Priori, Luigi A. VenetucciAbstract:RATIONALE: mutations of the ryanodine receptor (RyR) cause catecholaminergic polymorphic ventricular tachycardia (CPVT). These mutations predispose to the generation of Ca waves and delayed afterdepolarizations during Adrenergic stimulation. Ca waves occur when either sarcoplasmic reticulum (SR) Ca content is elevated above a threshold or the threshold is decreased. Which of these occurs in cardiac myocytes expressing CPVT mutations is unknown.\n\nOBJECTIVE: we tested whether the threshold SR Ca content is different between control and CPVT and how it relates to SR Ca content during β-Adrenergic stimulation.\n\nMETHODS AND RESULTS: ventricular myocytes from the RyR2 R4496C(+/-) mouse model of CPVT and wild-type (WT) controls were voltage-clamped; diastolic SR Ca content was measured and compared with the Ca wave threshold. The results showed the following. (1) In 1 mmol/L [Ca(2+)](o), β-Adrenergic stimulation with isoproterenol (1μmol/L) caused Ca waves only in R4496C. (2) SR Ca content and Ca wave threshold in R4496C were lower than those in WT. (3) β-Adrenergic stimulation increased SR Ca content by a similar amount in both R4496C and WT. (4) β-Adrenergic stimulation increased the threshold for Ca waves. (5) During β-Adrenergic stimulation in R4496C, but not WT, the increase of SR Ca was sufficient to reach threshold and produce Ca waves.\n\nCONCLUSIONS: in the R4496C CPVT model, the RyR is leaky, and this lowers both SR Ca content and the threshold for waves. β-Adrenergic stimulation produces Ca waves by increasing SR Ca content and not by lowering threshold.
Martin J Lohse - One of the best experts on this subject based on the ideXlab platform.
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altered expression of beta Adrenergic receptor kinase and beta 1 Adrenergic receptors in the failing human heart
Circulation, 1993Co-Authors: Martin Ungerer, M Bohm, J S Elce, E Erdmann, Martin J LohseAbstract:BACKGROUNDIn chronic heart failure, the positive inotropic effects of beta-Adrenergic receptor agonists are greatly reduced, in part as a result of two alterations of the cardiac beta-Adrenergic receptors: loss of their function (receptor uncoupling) and reduction of their number (downregulation). In vitro studies have shown that a major mechanism leading to beta-Adrenergic receptor uncoupling involves phosphorylation of the receptors by the specific beta-Adrenergic receptor kinase (beta ARK).METHODS AND RESULTSWe have therefore investigated expression of beta ARK and beta-Adrenergic receptors in samples from the left ventricles of patients with dilated cardiomyopathy or ischemic cardiomyopathy and from nonfailing control ventricles. Contractile responses to beta-receptor stimulation were decreased in the failing hearts compared with control hearts, whereas those to forskolin and calcium remained unchanged. The messenger RNA (mRNA) levels of beta ARK, beta 1- and beta 2-receptors, and of glyceraldehyde ph...
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beta arrestin a protein that regulates beta Adrenergic receptor function
Science, 1990Co-Authors: Martin J Lohse, Jeffrey L. Benovic, Marc G. Caron, J Codina, Robert J. LefkowitzAbstract:Homologous or agonist-specific desensitization of beta-Adrenergic receptors is thought to be mediated by a specific kinase, the beta-Adrenergic receptor kinase (beta ARK). However, recent data suggest that a cofactor is required for this kinase to inhibit receptor function. The complementary DNA for such a cofactor was cloned and found to encode a 418-amino acid protein homologous to the retinal protein arrestin. The protein, termed beta-arrestin, was expressed and partially purified. It inhibited the signaling function of beta ARK-phosphorylated beta-Adrenergic receptors by more than 75 percent, but not that of rhodopsin. It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-Adrenergic receptors.
Amanda Lochner - One of the best experts on this subject based on the ideXlab platform.
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A Role for the α_1-Adrenergic Signalling Pathway in the Response of Papillary Muscles from Type 2 Diabetic Hearts to Anoxia-Reoxygenation
Cardiovascular Drugs and Therapy, 2004Co-Authors: Barbara Huisamen, Jeanne Upton, Amanda LochnerAbstract:Hearts from animal models of type 2 diabetes present with abnormal contractility patterns. The role of altered α_1-Adrenergic signalling in this is not understood. In this study we report overexpression and altered regulation of α_1-Adrenergic receptors in two models of type 2 diabetic rat hearts. In combination with reduced contractile performance, papillary muscles from these hearts presented with an enhanced ability to react to α_1-Adrenergic stimulation. Concurrently, these muscles were protected against anoxia/reoxygenation induced damage. This protection could be abolished by pretreatment with the α_1-Adrenergic antagonist, prazosin. Overexpression of α_1-Adrenergic receptors may therefore be a two-edged sword: supplying a contractile reserve that can protect against anoxia/reoxygenation induced effects on inotropic ability on the one hand but also predisposing the hearts to elevated induction of intracellular Ca^2+ release and possible arrhythmic effects on the other hand.
Takeshi Kashimura - One of the best experts on this subject based on the ideXlab platform.
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In the RyR2R4496C mouse model of CPVT, β-Adrenergic stimulation induces ca waves by increasing SR Ca content and not by decreasing the threshold for Ca Waves
Circulation Research, 2010Co-Authors: Takeshi Kashimura, Sarah J. Briston, Carlo Napolitano, Andrew W. Trafford, David A. Eisner, Silvia G Priori, Luigi A. VenetucciAbstract:RATIONALE: mutations of the ryanodine receptor (RyR) cause catecholaminergic polymorphic ventricular tachycardia (CPVT). These mutations predispose to the generation of Ca waves and delayed afterdepolarizations during Adrenergic stimulation. Ca waves occur when either sarcoplasmic reticulum (SR) Ca content is elevated above a threshold or the threshold is decreased. Which of these occurs in cardiac myocytes expressing CPVT mutations is unknown.\n\nOBJECTIVE: we tested whether the threshold SR Ca content is different between control and CPVT and how it relates to SR Ca content during β-Adrenergic stimulation.\n\nMETHODS AND RESULTS: ventricular myocytes from the RyR2 R4496C(+/-) mouse model of CPVT and wild-type (WT) controls were voltage-clamped; diastolic SR Ca content was measured and compared with the Ca wave threshold. The results showed the following. (1) In 1 mmol/L [Ca(2+)](o), β-Adrenergic stimulation with isoproterenol (1μmol/L) caused Ca waves only in R4496C. (2) SR Ca content and Ca wave threshold in R4496C were lower than those in WT. (3) β-Adrenergic stimulation increased SR Ca content by a similar amount in both R4496C and WT. (4) β-Adrenergic stimulation increased the threshold for Ca waves. (5) During β-Adrenergic stimulation in R4496C, but not WT, the increase of SR Ca was sufficient to reach threshold and produce Ca waves.\n\nCONCLUSIONS: in the R4496C CPVT model, the RyR is leaky, and this lowers both SR Ca content and the threshold for waves. β-Adrenergic stimulation produces Ca waves by increasing SR Ca content and not by lowering threshold.
Jin Zhang - One of the best experts on this subject based on the ideXlab platform.
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insulin disrupts β Adrenergic signalling to protein kinase a in adipocytes
Nature, 2005Co-Authors: Jin Zhang, Christopher J Hupfeld, Susan S Taylor, Jerrold M Olefsky, Roger Y TsienAbstract:Hormones mobilize intracellular second messengers and initiate signalling cascades involving protein kinases and phosphatases, which are often spatially compartmentalized by anchoring proteins to increase signalling specificity1. These scaffold proteins may themselves be modulated by hormones2,3,4. In adipocytes, stimulation of β-Adrenergic receptors increases cyclic AMP levels and activates protein kinase A (PKA)5, which stimulates lipolysis by phosphorylating hormone-sensitive lipase and perilipin6,7,8. Acute insulin treatment activates phosphodiesterase 3B, reduces cAMP levels and quenches β-Adrenergic receptor signalling9. In contrast, chronic hyperinsulinaemic conditions (typical of type 2 diabetes) enhance β-Adrenergic receptor-mediated cAMP production10. This amplification of cAMP signalling is paradoxical because it should enhance lipolysis, the opposite of the known short-term effect of hyperinsulinaemia. Here we show that in adipocytes, chronically high insulin levels inhibit β-Adrenergic receptors (but not other cAMP-elevating stimuli) from activating PKA. We measured this using an improved fluorescent reporter and by phosphorylation of endogenous cAMP-response-element binding protein (CREB). Disruption of PKA scaffolding mimics the interference of insulin with β-Adrenergic receptor signalling. Chronically high insulin levels may disrupt the close apposition of β-Adrenergic receptors and PKA, identifying a new mechanism for crosstalk between heterologous signal transduction pathways.
