title: Genetic deletion of Rnd3/RhoE results in mouse heart calcium leakage through upregulation of protein kinase A signaling.
abstract: BACKGROUND
  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.
  
  
  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 β2-adrenergic receptor lysosomal targeting and ubiquitination, which in turn resulted in the elevation of β2-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. β2-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 β2-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.
authors.affiliation: Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston, TX 77030.
authors.forename: Xiangsheng
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Molecular Physiology & Biophysics, and Medicine (Cardiology), Baylor College of Medicine, Houston, TX 77030.
authors.forename: Tiannan
authors.initials: T
authors.lastname: Wang
authors.affiliation: Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston, TX 77030.
authors.forename: Xi
authors.initials: X
authors.lastname: Lin
authors.affiliation: Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston, TX 77030.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Yue
authors.affiliation: Department of Molecular Physiology & Biophysics, and Medicine (Cardiology), Baylor College of Medicine, Houston, TX 77030.
authors.forename: Qiongling
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Molecular Physiology & Biophysics, and Medicine (Cardiology), Baylor College of Medicine, Houston, TX 77030.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, University of California at Davis, CA 95616.
authors.forename: Qin
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153.
authors.forename: Xun
authors.initials: X
authors.lastname: Ai
authors.affiliation: Department of Molecular Physiology & Biophysics, and Medicine (Cardiology), Baylor College of Medicine, Houston, TX 77030.
authors.forename: David Y
authors.initials: DY
authors.lastname: Chiang
authors.affiliation: Texas Children's Hospital, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Christina Y
authors.initials: CY
authors.lastname: Miyake
authors.affiliation: Department of Molecular Physiology & Biophysics, and Medicine (Cardiology), Baylor College of Medicine, Houston, TX 77030.
authors.forename: Xander H T
authors.initials: XHT
authors.lastname: Wehrens
authors.affiliation: Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston, TX 77030.
authors.forename: Jiang
authors.initials: J
authors.lastname: Chang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis*; D005260:Female; D017353:Gene Deletion; D006321:Heart / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000172:deficiency* / Q000235:genetics*
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases; C513341:Rnd3 protein, mouse; D020741:rho GTP-Binding Proteins; D002118:Calcium
keywords: adrenergic receptor, beta-2; arrhythmias, cardiac; calcium; rho GTP-binding proteins; ubiquitination