Genetic deletion of Rnd3/RhoE results in mouse heart calcium leakage through upregulation of protein kinase A signaling. Academic Article uri icon


  • RATIONALE: 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 2-adrenergic receptor lysosomal targeting and ubiquitination, which in turn resulted in the elevation of 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. 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 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.

published proceedings

  • Circ Res

altmetric score

  • 0.75

author list (cited authors)

  • Yang, X., Wang, T., Lin, X. i., Yue, X., Wang, Q., Wang, G., ... Chang, J.

citation count

  • 24

complete list of authors

  • Yang, Xiangsheng||Wang, Tiannan||Lin, Xi||Yue, Xiaojing||Wang, Qiongling||Wang, Guoliang||Fu, Qin||Ai, Xun||Chiang, David Y||Miyake, Christina Y||Wehrens, Xander HT||Chang, Jiang

publication date

  • January 2015