Genetic deletion of Rnd3/RhoE results in mouse heart calcium leakage through upregulation of protein kinase A signaling Journal Article

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Authors: Yang, X.; Wang, T; Lin, X; Yue, X.; Wang, Q.; Wang, G; Fu, Q.; Ai, X; Chiang, D. Y.; Miyake, C. Y.; Wehrens, X. H.; Chang, J.
Article Title: Genetic deletion of Rnd3/RhoE results in mouse heart calcium leakage through upregulation of protein kinase A signaling
Abstract: 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 beta2-adrenergic receptor lysosomal targeting and ubiquitination, which in turn resulted in the elevation of beta2-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. beta2-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 beta2-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.
Journal Title: Circulation research
Volume: 116
Issue: 1
ISSN: 1524-4571; 0009-7330
Publisher: American Heart Association, Inc  
Journal Place: United States
Date Published: 2015
Start Page: e1
End Page: e10
Language: eng
DOI/URL:

10.1161/CIRCRESAHA.116.304940
Notes: LR: 20150113; CI: (c) 2014; GR: K02 HL098956/HL/NHLBI NIH HHS/United States; GR: K02HL098956/HL/NHLBI NIH HHS/United States; GR: R01 HL102314/HL/NHLBI NIH HHS/United States; GR: R01 HL113640/HL/NHLBI NIH HHS/United States; GR: R01 HL123953/HL/NHLBI NIH HHS/United States; GR: R01HL089598/HL/NHLBI NIH HHS/United States; GR: R01HL091947/HL/NHLBI NIH HHS/United States; GR: R01HL102314/HL/NHLBI NIH HHS/United States; GR: R01HL113640/HL/NHLBI NIH HHS/United States; GR: R21 HL094844/HL/NHLBI NIH HHS/United States; GR: R21HL094844/HL/NHLBI NIH HHS/United States; JID: 0047103; NIHMS638385; OID: NLM: NIHMS638385 [Available on 01/02/16]; OID: NLM: PMC4282622 [Available on 01/02/16]; OTO: NOTNLM; PMCR: 2016/01/02 00:00; 2014/10/27 [aheadofprint]; ppublish