Enhancement of the recycling and activation of β‐adrenergic receptor by Rab4 GTPase in cardiac myocytes

Abstract

We investigated the role of Rab4, a Ras-like small GTPase which coordinates protein transport specifically from the endosome to the plasma membrane, in the recycling and activation of endogenous β-adrenergic receptor (β-AR) in HL-1 cardiac myocytes in vitro and transgenic mouse hearts in vivo. β 1-AR, the predominant subtype of β-AR in HL-1 myocytes, is internalized after stimulation with isoproterenol (ISO) and fully recycled at 4 hrs upon ISO removal. Transient expression of Rab4 markedly facilitated recycling of internalized β-AR to the cell surface and enhanced β-AR signaling as measured by ISO-stimulated cAMP production. Transgenic overexpression of Rab4 in the mouse myocardium significantly increased the number of β-AR in the plasma membrane and augmented cAMP production at the basal level and in response to ISO stimulation. Rab4 overexpression induced concentric cardiac hypertrophy with a moderate increase in ventricle/body weight ratio and posterior wall thickness and a selective upregulation of the β-myosin heavy chain gene. These data provide the first evidence indicating that Rab4 is a rate-limiting factor for the recycling of endogenous β-AR and augmentation of Rab4-mediated traffic enhances β-AR function in cardiac myocytes (P20RR018766).