β-Adrenergic receptor activation induces internalization of cardiac Cav1.2 channel complexes through a β-arrestin 1-mediated pathway

Rachele Lipsky, Essie M. Potts, Sima T. Tarzami, Akil A. Puckerin, Joanne Stocks, Alison D. Schecter, Eric A. Sobie, Fadi G. Akar, María A. Diversé-Pierluissi

Research output: Contribution to journalArticlepeer-review

Abstract

Voltage-dependent calcium channels (VDCCs) play a pivotal role in normal excitation-contraction coupling in cardiac myocytes. These channels can be modulated through activation of β-adrenergic receptors (β-ARs), which leads to an increase in calcium current (ICa-L) density through cardiac Cav1 channels as a result of phosphorylation by cAMP-dependent protein kinase A. Changes in ICa-L density and kinetics in heart failure often occur in the absence of changes in Ca v1 channel expression, arguing for the importance of posttranslational modification of these channels in heart disease. The precise molecular mechanisms that govern the regulation of VDCCs and their cell surface localization remain unknown. Our data show that sustained β-AR activation induces internalization of a cardiac macromolecular complex involving VDCC and β-arrestin 1 (β-Arr1) into clathrin-coated vesicles. Pretreatment of myocytes with pertussis toxin prevents the internalization of VDCCs, suggesting that Gi/o mediates this response. A peptide that selectively disrupts the interaction between CaV1.2 and β-Arr1 and tyrosine kinase inhibitors readily prevent agonist-induced VDCC internalization. These observations suggest that VDCC trafficking is mediated by G protein switching to Gi of the β-AR, which plays a prominent role in various cardiac pathologies associated with a hyperadrenergic state, such as hypertrophy and heart failure.

Original languageEnglish (US)
Pages (from-to)17221-17226
Number of pages6
JournalJournal of Biological Chemistry
Volume283
Issue number25
DOIs
StatePublished - Jun 20 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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