In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 116, No. 1 ( 2015-01-02)
Abstract:
Rnd3, a small Rho GTPase, is involved in the regulation of cell actin cytoskeleton dynamics, cell migration, and proliferation. The biological function of Rnd3 in the heart remains unexplored. Objective: To define the functional role of the Rnd3 gene in the animal heart and investigate the associated molecular mechanism. Methods and Results: By loss-of-function approaches, we discovered that Rnd3 is involved in calcium regulation in cardiomyocytes. Rnd3-null mice died at the embryonic stage with fetal arrhythmias. The deletion of Rnd3 resulted in severe Ca 2+ leakage through destabilized ryanodine receptor type 2 Ca 2+ release channels. We further found that downregulation of Rnd3 attenuated β 2 -adrenergic receptor lysosomal targeting and ubiquitination, which in turn resulted in the elevation of β 2 -adrenergic receptor protein levels leading to the hyperactivation of protein kinase A (PKA) signaling. The PKA activation destabilized ryanodine receptor type 2 channels. This irregular spontaneous Ca 2+ release can be curtailed by PKA inhibitor treatment. Increases in the PKA activity along with elevated cAMP levels were detected in Rnd3-null embryos, in neonatal rat cardiomyocytes, and noncardiac cell lines with Rnd3 knockdown, suggesting a general mechanism for Rnd3-mediated PKA signaling activation. β 2 -Adrenergic receptor blocker treatment reduced arrhythmia and improved cardiac function. Conclusions: Rnd3 is a novel factor involved in intracellular Ca 2+ homeostasis regulation in the heart. Deficiency of the protein induces ryanodine receptor type 2 dysfunction by a mechanism that attenuates Rnd3-mediated β 2 -adrenergic receptor ubiquitination, which leads to the activation of PKA signaling. Increased PKA signaling in turn promotes ryanodine receptor type 2 hyperphosphorylation, which contributes to arrhythmogenesis and heart failure.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/CIRCRESAHA.116.304940
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2015
detail.hit.zdb_id:
1467838-X
