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GRK2 blockade with βARKct is essential for cardiac β2-adrenergic receptor signaling towards increased contractility

Norma C Salazar1, Ximena Vallejos, Ashley Siryk

  • 1Department of Pharmaceutical Sciences, Laboratory for the Study of Neurohormonal Control of the Circulation, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328, USA. al806@nova.edu.

Cell Communication and Signaling : CCS
|August 30, 2013
PubMed
Abstract

Insights

Blocking G protein coupled receptor kinase 2 (GRK2) is essential for enhancing cardiac beta-2 adrenergic receptor (β2AR) pro-contractile signaling. This inhibition also temporarily boosts β2AR anti-apoptotic effects in heart failure models.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Pharmacology

Background:

  • Beta-1 and beta-2 adrenergic receptors (ARs) have distinct cardiac roles; β1AR is pro-contractile/pro-apoptotic, while β2AR is anti-apoptotic and weakly pro-contractile.
  • G protein coupled receptor kinase (GRK)-2 desensitizes βARs via phosphorylation and beta-arrestin (βarr) binding, opposing pro-contractile signaling.
  • This study investigated if GRK2 blockade could enhance cardiac β2AR pro-contractile signaling.

Purpose of the Study:

  • To determine if cardiac-targeted GRK2 inhibition enhances β2AR pro-contractile signaling in vivo.
  • To examine the effects of GRK2 inhibition on β2AR signaling under normal conditions and in heart failure (HF).

Main Methods:

  • Crossed β1AR knockout (B1KO) mice with cardiac-specific transgenic mice expressing the GRK2 inhibitor, βARKct.
  • Studied offspring under normal conditions and post-myocardial infarction (MI).
  • Assessed β2AR-dependent contractile function and survival rates.

Main Results:

  • Cardiac βARKct expression was essential for β2AR-dependent contractility; β2AR stimulation only increased contractility in the presence of βARKct.
  • GRK2 inhibition released the molecular brake on β2AR signaling by blocking phosphodiesterase type 4D (PDE4D) interaction with β2AR.
  • βARKct increased survival in post-MI B1KO mice by reducing apoptosis and increasing early inflammation, though these effects diminished by 4 weeks with GRK5 upregulation.

Conclusions:

  • In vivo GRK2 inhibition using βARKct is critical for cardiac β2AR pro-contractile signaling and function.
  • β2AR anti-apoptotic signaling in post-MI HF is augmented by βARKct, but this effect is transient.

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