scholarly journals Beta-adrenergic receptor-G protein-adenylate cyclase complex in experimental canine congestive heart failure produced by rapid ventricular pacing.

1991 ◽  
Vol 69 (6) ◽  
pp. 1546-1556 ◽  
Author(s):  
K P Marzo ◽  
M J Frey ◽  
J R Wilson ◽  
B T Liang ◽  
D R Manning ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Adenylate Cyclase ◽  
G Protein ◽  
Adrenergic Receptor ◽  
Ventricular Pacing ◽  
Beta Adrenergic Receptor ◽  
Beta Adrenergic ◽  
Rapid Ventricular Pacing ◽  
Experimental Canine

scholarly journals Beta-adrenergic receptor blocking therapy for congestive heart failure: an overview

2000 ◽  
Vol 1 ◽  
pp. 6-8
Author(s):  
JC Mohan
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Adrenergic Receptor ◽  
Symptomatic Relief ◽  
Blocking Agent ◽  
Symptomatic Improvement ◽  
Beta Adrenergic Receptor ◽  
Remarkable Change ◽  
Beta Adrenergic ◽  
Receptor Blocking

It is uncommon for clinical trials to be prematurely terminated because of formidable evidence in favour ofa particular agent or strategy and rare for such trials to be reported in lay press. This is what has precisely happened with regard to beta-adrenoceptor blocking therapy in patients with congestive heart failure twice once in 1996 and again in March, 2000. The drug in question has been carvedilol (a beta-adrenergic receptor blocking agent) and the trials were Carvedilol US Heart Failure Study and GOPERNICUS (Carvedilol Prospective Randomised Cumulative Outcome Study). The therapy in patients of congestive heart failure has shown a remarkable change over a period of last three decades ever since it was shown by a Swedish team that in some patients with heart failure, beta-blocking agents can cause symptomatic improvement in refractory heart failure. The current theme is no longer symptomatic relief which is variable butsurvival benefits and less need for cardiac transplantation and recurrent hospitalization.Saga of beta-blocker therapy taught us how mechanistic approach and experimental data do not always provide the correct answer to a complex pathophysiological syndrome.

Abstract 207: Left Ventricular Assist Device (LVAD) Reverses Inhibition on Beta-adrenergic Receptor Resensitization

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Elizabeth E Martelli ◽  
Arunachal Chatterjee ◽  
Randall Starling ◽  
Christine Moravec ◽  
Sathyamangla V Naga Prasad
Keyword(s):  
Heart Failure ◽  
G Protein ◽  
Adrenergic Receptor ◽  
Human Heart ◽  
Plasma Membranes ◽  
Left Ventricular ◽  
Beta Adrenergic Receptor ◽  
Beta Adrenergic ◽  
Pp2a Activity ◽  
Pi3k Activity

Beta-adrenergic receptor (βAR) down-regulation and desensitization are hallmarks of heart failure. Agonist occupied βAR undergo desensitization through phosphorylation by G-protein coupled receptor kinases leading to βAR internalization. Phosphorylated βAR becomes resensitized following dephosphorylation by protein phosphatase 2A (PP2A) in the endosomes and we have shown previously shown that PP2A activity is regulated by phosphoinositide3-kinaseγ (PI3Kγ). Traditionally, it has been considered that increased desensitization mechanisms underlie βAR dysfunction in heart failure but it is not known whether resensitization of βARs is altered and an integral contributor to heart failure. To test whether resensitization mechanisms are altered in heart failure and could play a role in recovery of βAR function post-LVAD, we used paired pre- and post-LVAD human heart samples along with non-failing hearts. Since resensitization occurs in endosomes, plasma membranes and endosomes were isolated from these human heart samples and assessed for PI3K activity, PP2A activity, β2AR phosphorylation and adenylyl cyclase (AC) activity as a measure of recovery in βAR function by G-protein coupling. Significant PI3Kγ activity was observed in the endosomes of pre-LVAD compared post-LVAD and non-failing human heart samples while plasma membrane PI3K activity remained similar across all samples. Similarly, AC activity was markedly reduced in plasma membranes and endosomes of pre-LVAD samples compared to post-LVAD and non-failing showing reduced ability of receptors to couple to G-proteins indicating reduced recovery of receptor function in post-LVAD heart samples. Consistent with the reduced recovery in βAR function in pre-LVAD samples, significant β2AR phosphorylation was observed in the endosomes and plasma membranes of pre-LVAD compared to post-LVAD and non-failing. Correspondingly, we observed significant reduction in endosomal PP2A activity in the pre-LVAD samples which was remarkably reversed in post-LVAD samples similar to the activity in non-failing. These studies suggest that resensitization is inhibited in end-stage human heart failure and may critically contribute to cardiac remodeling and hypertrophic response upon cardiac stress.

scholarly journals G-protein-mediated activation of turkey erythrocyte phospholipase C by β-adrenergic and P2y-purinergic receptors

1992 ◽  
Vol 284 (3) ◽  
pp. 917-922 ◽  
Author(s):  
C Vaziri ◽  
C P Downes
Keyword(s):  
Adenylate Cyclase ◽  
Phospholipase C ◽  
G Protein ◽  
Adrenergic Receptor ◽  
Purinergic Receptor ◽  
Single Species ◽  
Erythrocyte Membranes ◽  
Dependent Manner ◽  
Beta Adrenergic Receptor ◽  
Beta Adrenergic

Isoprenaline, previously known only to stimulate adenylate cyclase via the stimulatory G-protein, Gs, activates turkey erythrocyte ghost phospholipase C (PLC) in a dose-dependent manner when GTP or guanosine 5′-[gamma-thio]triphosphate (GTP[S]) is present. The effect is specific in that it is abolished by beta-adrenergic-receptor antagonists. Stimulation of adenosine receptors, which also couple to adenylate cyclase via Gs in turkey erythrocytes, does not activate PLC, indicating that the stimulation observed in the presence of isoprenaline is not due to Gs activation. Furthermore, the stimulation seen is independent of cyclic AMP production. Purified turkey erythrocyte PLC is activated in an adenosine 5′-[beta-thio]diphosphate (ADP[S]; a P2y-purinergic-receptor agonist)- or isoprenaline-regulated manner when reconstituted with turkey erythrocyte ghosts, demonstrating that a single species of PLC effector enzyme can be regulated by both the purinergic and the beta-adrenergic receptor populations present in turkey erythrocyte membranes. Pretreatment of intact turkey erythrocytes with the P2y agonist ADP[S] causes decreased PLC responsiveness of subsequent ghost preparations to ADP[S] stimulation, although responses to isoprenaline are unaffected (homologous desensitization). In contrast, pretreatment of intact erythrocytes with isoprenaline results in heterologous desensitization of both the P2y and the beta-adrenergic receptors. These effects occur at the level of receptor-G-protein coupling, since PLC stimulation by GTP[S] (which directly activates G-proteins) in the absence of agonists is unaffected.

scholarly journals The turkey erythrocyte β-adrenergic receptor couples to both adenylate cyclase and phospholipase C via distinct G-protein α subunits

1994 ◽  
Vol 304 (2) ◽  
pp. 359-364 ◽  
Author(s):  
S R James ◽  
C Vaziri ◽  
T R Walker ◽  
G Milligan ◽  
C P Downes
Keyword(s):  
Adenylate Cyclase ◽  
Phospholipase C ◽  
G Protein ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Inositol Phosphates ◽  
Adenosine Monophosphate ◽  
Beta Adrenergic Receptors ◽  
Beta Adrenergic Receptor ◽  
Beta Adrenergic

By contrast with mammalian beta-adrenergic receptors, the avian isoform elicits two distinct effector responses, activation of adenylate cyclase and polyphosphoinositide-specific phospholipase C (PLC) leading to the accumulation of both cyclic adenosine monophosphate (cyclic AMP) and inositol phosphates. We have investigated the mechanisms of beta-adrenergic receptor signalling in turkey erythrocytes. Stimulation of adenylate cyclase by the beta-adrenergic-receptor agonist isoprenaline exhibits a 30-fold lower EC50 than that for PLC activation, which may indicate a marked receptor reserve for the former effector. Similar Ki values were obtained for the inhibition of both responses by four beta-adrenergic antagonists, arguing that a single receptor population is responsible for both effects. Antibodies raised against G-protein peptide sequences were used to show that the identity of the G-protein mediating the PLC response was an avian homologue of G11, the level of expression of which was very similar to that of the stimulatory G-protein of adenylate cyclase, Gs. Thus a single population of beta-adrenergic receptors apparently interacts with distinct G-proteins to activate different effectors. The stoichiometries of the receptor-G-protein-effector interactions are therefore similar for both second-messenger responses and the data are discussed in terms of the different efficacies observed for each response.

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