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G??-independent recruitment of G-protein coupled receptor kinase 2 drives tumor necrosis factor ?-induced cardiac ?-adrenergic receptor dysfunction.

ABSTRACT: Proinflammatory cytokine tumor necrosis factor-? (TNF?) induces ?-adrenergic receptor (?AR) desensitization, but mechanisms proximal to the receptor in contributing to cardiac dysfunction are not known.Two different proinflammatory transgenic mouse models with cardiac overexpression of myotrophin (a prohypertrophic molecule) or TNF? showed that TNF? alone is sufficient to mediate ?AR desensitization as measured by cardiac adenylyl cyclase activity. M-mode echocardiography in these mouse models showed cardiac dysfunction paralleling ?AR desensitization independent of sympathetic overdrive. TNF?-mediated ?AR desensitization that precedes cardiac dysfunction is associated with selective upregulation of G-protein coupled receptor kinase 2 (GRK2) in both mouse models. In vitro studies in ?2AR-overexpressing human embryonic kidney 293 cells showed significant ?AR desensitization, GRK2 upregulation, and recruitment to the ?AR complex following TNF?. Interestingly, inhibition of phosphoinositide 3-kinase abolished GRK2-mediated ?AR phosphorylation and GRK2 recruitment on TNF?. Furthermore, TNF?-mediated ?AR phosphorylation was not blocked with ?AR antagonist propranolol. Additionally, TNF? administration in transgenic mice with cardiac overexpression of G??-sequestering peptide ?ARK-ct could not prevent ?AR desensitization or cardiac dysfunction showing that GRK2 recruitment to the ?AR is G?? independent. Small interfering RNA knockdown of GRK2 resulted in the loss of TNF?-mediated ?AR phosphorylation. Consistently, cardiomyocytes from mice with cardiac-specific GRK2 ablation normalized the TNF?-mediated loss in contractility, showing that TNF?-induced ?AR desensitization is GRK2 dependent.TNF?-induced ?AR desensitization is mediated by GRK2 and is independent of G??, uncovering a hitherto unknown cross-talk between TNF? and ?AR function, providing the underpinnings of inflammation-mediated cardiac dysfunction.

SUBMITTER: Vasudevan NT

PROVIDER: S-EPMC3874808 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Gβγ-independent recruitment of G-protein coupled receptor kinase 2 drives tumor necrosis factor α-induced cardiac β-adrenergic receptor dysfunction.

Vasudevan Neelakantan T NT Mohan Maradumane L ML Gupta Manveen K MK Martelli Elizabeth E EE Hussain Afshan K AK Qin Yilu Y Chandrasekharan Unni M UM Young David D Feldman Arthur M AM Sen Subha S Dorn Gerald W GW Dicorleto Paul E PE Naga Prasad Sathyamangla V SV

Circulation 20130619 4

<h4>Background</h4>Proinflammatory cytokine tumor necrosis factor-α (TNFα) induces β-adrenergic receptor (βAR) desensitization, but mechanisms proximal to the receptor in contributing to cardiac dysfunction are not known.<h4>Methods and results</h4>Two different proinflammatory transgenic mouse models with cardiac overexpression of myotrophin (a prohypertrophic molecule) or TNFα showed that TNFα alone is sufficient to mediate βAR desensitization as measured by cardiac adenylyl cyclase activity. ...[more]

PMID: 23785004

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Dataset Information

G??-independent recruitment of G-protein coupled receptor kinase 2 drives tumor necrosis factor ?-induced cardiac ?-adrenergic receptor dysfunction.

Publications

Gβγ-independent recruitment of G-protein coupled receptor kinase 2 drives tumor necrosis factor α-induced cardiac β-adrenergic receptor dysfunction.

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