Regulation of cardiac contractility by Rab4-modulated β2-adrenergic receptor recycling

Amy Odley, Harvey S. Hahn, Roy A. Lynch, Yehia Marreez, Hanna Osinska, Jeffrey Robbins, Gerald W. Dorn

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

Catecholaminergic activation of myocardial β-adrenergic receptors (βAR) is the principle mechanism regulating cardiac function. Agonists desensitize βAR through G protein-coupled receptor kinase-mediated uncoupling and β-arrestin-mediated internalization. Although inhibition of myocardial G protein-coupled receptor kinase-2 enhances cardiac function and reverses heart failure, pathophysiological effects of modulated βAR internalization/recycling are unknown. We used mutation and transgenic expression of Rab4, which regulates vesicular transport of heptahelical receptors to plasma membranes, to interrogate in vivo βAR trafficking and cardiac function. Expression of constitutively active Rab4 Q72L had no effects on cardiac structure or function, but dominant inhibitor Rab4 S27N impaired responsiveness to endogenous and exogenous catecholamines. To relate βAR trafficking to diminished cardiac function, Rab4 mutant mice were crossbred with mice overexpressing human β2AR. In unstimulated β2AR overexpressors, β2AR localized to heavier endosomes and translocated to lighter, caveolin-rich fractions after isoproterenol stimulation. Co-expression of β2AR with activated Rab4 Q72L caused loss of receptors from heavier endosomes while retaining normal inotropy. In contrast, coexpression of β2AR with inhibitory Rab4 S27N mimicked isoproterenol-induced receptor redistribution to caveolae, with diminished cardiac inotropy. Rab4 inhibition alone prevented resensitization after isoproterenol-induced in vivo adrenergic desensitization. Confocal and ultrastructural analyses revealed bizarre vesicular structures and abnormal accumulation of β2AR in the sarcoplasm and subsarcollema of Rab4 S27N, but not Q72L, mice. These data provide evidence for constant bidirectional sarcollemal-vesicular βAR trafficking in the in vivo heart and show that Rab4-mediated recycling of internalized βAR is necessary for normal cardiac catecholamine responsiveness and resensitization after agonist exposure.

Original languageEnglish
Pages (from-to)7082-7087
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number18
DOIs
StatePublished - May 4 2004
Externally publishedYes

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