Gi Protein-mediated Functional Compartmentalization of Cardiac β2-Adrenergic Signaling

Kuschel, Meike; Zhou, Ying; Cheng, Heping; Zhang, Sheng Jun; Chen, Ye; Lakatta, Edward G.; Xiao, Rui

doi:10.1074/jbc.274.31.22048

Cited by 159 publications

(143 citation statements)

References 31 publications

(53 reference statements)

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“…Alternatively, other studies performed in rat, dog, and mouse hearts have suggested a dual coupling of ␤ 2 -AR to concurrent G s and PTX-sensitive G i signaling pathways (45)(46)(47). In those species, the ␤ 2 -AR/G i pathway seems to exert a negative control on the ␤ 2 -AR/G s pathway.…”

Section: Discussionmentioning

confidence: 99%

β2-Adrenergic Receptor Agonists Increase Intracellular Free Ca2+ Concentration Cycling in Ventricular Cardiomyocytes through p38 and p42/44 MAPK-mediated Cytosolic Phospholipase A2 Activation

Magne

Couchie

Pecker

et al. 2001

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

β2-Adrenergic Receptor Agonists Increase Intracellular Free Ca2+ Concentration Cycling in Ventricular Cardiomyocytes through p38 and p42/44 MAPK-mediated Cytosolic Phospholipase A2 Activation

Magne

Couchie

Pecker

et al. 2001

Journal of Biological Chemistry

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“…Fractionation studies show that ␤ 2 ARs are concentrated in caveolae structures, whereas ␤ 1 ARs are mainly distributed in non-caveolar membrane on the cardiac myocyte plasma membrane (9,10). Moreover, studies show that ␤ 2 AR signaling can modulate L-type Ca 2ϩ channel activity in distinct subcellular microdomains in hippocampal neurons and cardiac myocytes (11)(12)(13). These observations suggest that distinct signaling complexes may exist in cardiac myocytes to conduct ␤ 1 and ␤ 2 AR signaling.…”

mentioning

confidence: 92%

The PDZ Binding Motif of the β1 Adrenergic Receptor Modulates Receptor Trafficking and Signaling in Cardiac Myocytes

Xiang¹,

Devic

Kobilka

2002

Journal of Biological Chemistry

104

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␤ 1 and ␤ 2 adrenergic receptors (AR) regulate the intrinsic contraction rate in neonatal mouse cardiac myocytes through distinct signaling pathways. It has been shown that stimulation of ␤ 1 ARs leads to a protein kinase A-dependent increase in contraction rate. In contrast, stimulation of ␤ 2 ARs has a biphasic effect on contraction rate, with an initial protein kinase A-independent increase followed by a sustained decrease that is blocked by pertussis toxin. The ␤ 2 AR undergoes agonist-induced endocytosis in cardiac myocytes while the ␤ 1 AR remains on the cell surface. It has been shown that a PDZ domain binding motif at the carboxyl terminus of ␤ 1 AR interacts with the postsynaptic density protein PSD-95 when both are expressed in HEK293 cells. We found that mutation of this PDZ binding motif in the ␤ 1 AR (␤ 1 AR-PDZ) enabled agonist-induced internalization in cardiac myocytes. Moreover, stimulation of ␤ 1 AR-PDZ had a biphasic effect on the myocyte contraction rate similar to that observed following stimulation of the ␤ 2 AR. The secondary decrease in the contraction rate was mediated by G i and could be blocked by pertussis toxin. Furthermore, a non-selective endocytosis inhibitor, concanavalin A, inhibited the internalization of wild type ␤ 2 AR and the mutated ␤ 1 AR-PDZ, and blocked the coupling of both receptors to G i . Finally, treating myocytes with a membrane-permeable peptide representing ␤ 1 AR PDZ motif caused the endogenous ␤ 1 AR to behave like ␤ 1 AR-PDZ. These studies suggest that association of the ␤ 1 AR with PSD-95 or a related protein dictates signaling specificity by retaining the receptor at the cell surface and preventing interaction with G i .␤ adrenergic receptors (␤ 1 AR, ␤ 2 AR, and ␤ 3 AR) 1 are heptahelical G protein-coupled receptors (GPCRs) that mediate physiological responses to the hormone epinephrine and the neurotransmitter norepinephrine. Both ␤ 1 and ␤ 2 ARs are expressed in the heart and play critical roles in regulating cardiac function in animals (1). In vitro studies show that ␤ 1 and ␤ 1 ARs have very similar signaling properties when expressed in undifferentiated cell lines (2). However, evidence also suggests that they have different signaling properties in differentiated cells in vivo (3, 4). Moreover, these receptors may differ in other functional parameters such as desensitization (5). ␤ 1 AR knockout mice lack the normal inotropic and chronotropic response to the adrenergic agonist, isoproterenol (6), whereas these responses are preserved in ␤ 2 AR knockout mice (7).We recently reported that ␤ 1 and ␤ 2 ARs regulate contraction rate in mouse neonatal myocytes through different signal transduction pathways (8). Activated ␤ 1 AR couples only to G s and leads to a PKA-dependent increase in contraction rate. Activated ␤ 2 AR undergoes sequential coupling to G s and G i and has a biphasic effect on contraction rate, with an initial PKAindependent increase followed by a sustained decrease that can be blocked by pertussis toxin (8). Recent biochemical evidence su...

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“…β 1 ARs and β 2 ARs signal through Gα s and AC with similar efficacy. However, the signals are compartmentalized differently in cardiomyocytes, possibly due to their localization in distinct membrane microdomains and/or dual coupling of the β 2 AR to Gα s and Gα i [3]. β 2 ARs also have a high level of spontaneous activity not detected for β 1 AR [4].…”

Section: Introductionmentioning

confidence: 99%

Nuclear β-adrenergic receptors modulate gene expression in adult rat heart

Vaniotis

Duca

Trieu

et al. 2011

Cellular Signalling

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Both β 1 -and β 3 -adrenergic receptors (β 1 ARs and β 3 ARs) are present on nuclear membranes in adult ventricular myocytes. These nuclear-localized receptors are functional with respect to ligand binding and effector activation. In isolated cardiac nuclei, the non-selective βAR agonist isoproterenol stimulated de novo RNA synthesis measured using assays of transcription initiation (Boivin et al., 2006 Cardiovasc Res. 71:69-78). In contrast, stimulation of endothelin receptors, another G protein-coupled receptor (GPCR) that localizes to the nuclear membrane, resulted in decreased RNA synthesis. To investigate the signalling pathway(s) involved in GPCR-mediated regulation of RNA synthesis, nuclei were isolated from intact adult rat hearts and treated with receptor agonists in the presence or absence of inhibitors of different mitogen-activated protein kinase (MAPK) and PI3K/PKB pathways. Components of p38, JNK, and ERK1/2 MAP kinase cascades as well as PKB were detected in nuclear preparations. Inhibition of PKB with triciribine, in the presence of isoproterenol, converted the activation of the βAR from stimulatory to inhibitory with regards to RNA synthesis, while ERK1/2, JNK and p38 inhibition reduced both basal and isoproterenol-stimulated activity. Analysis by qPCR indicated an increase in the expression of 18 S rRNA following isoproterenol treatment and a decrease in NFκB mRNA. Further qPCR experiments revealed that isoproterenol treatment also reduced the expression of several other genes involved in the activation of NFκB, while ERK1/2 and PKB inhibition substantially * Corresponding authors. Hébert is to be contacted

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Gi Protein-mediated Functional Compartmentalization of Cardiac β2-Adrenergic Signaling

Cited by 159 publications

References 31 publications

β2-Adrenergic Receptor Agonists Increase Intracellular Free Ca2+ Concentration Cycling in Ventricular Cardiomyocytes through p38 and p42/44 MAPK-mediated Cytosolic Phospholipase A2 Activation

β2-Adrenergic Receptor Agonists Increase Intracellular Free Ca2+ Concentration Cycling in Ventricular Cardiomyocytes through p38 and p42/44 MAPK-mediated Cytosolic Phospholipase A2 Activation

The PDZ Binding Motif of the β1 Adrenergic Receptor Modulates Receptor Trafficking and Signaling in Cardiac Myocytes

Nuclear β-adrenergic receptors modulate gene expression in adult rat heart

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