Molecular Bases of Disease
Endoplasmic Reticulum Stress and Ca2+ Depletion Differentially Modulate the Sterol Regulatory Protein PCSK9 to Control Lipid Metabolism
Accumulating evidence implicates endoplasmic reticulum (ER) stress as a mediator of impaired lipid metabolism, thereby contributing to fatty liver disease and atherosclerosis. Previous studies demonstrated that ER stress can activate the sterol regulatory element-binding protein-2 (SREBP2), an ER-localized transcription factor that directly up-regulates sterol regulatory genes, including PCSK9. Given that PCSK9 contributes to atherosclerosis by targeting low density lipoprotein (LDL) receptor (LDLR) degradation, this study investigates a novel mechanism by which ER stress plays a role in lipid metabolism by examining its ability to modulate PCSK9 expression.The Arrhythmogenic Calmodulin p.Phe142Leu Mutation Impairs C-domain Ca2+ Binding but Not Calmodulin-dependent Inhibition of the Cardiac Ryanodine Receptor
A number of point mutations in the intracellular Ca2+-sensing protein calmodulin (CaM) are arrhythmogenic, yet their underlying mechanisms are not clear. These mutations generally decrease Ca2+ binding to CaM and impair inhibition of CaM-regulated Ca2+ channels like the cardiac Ca2+ release channel (ryanodine receptor, RyR2), and it appears that attenuated CaM Ca2+ binding correlates with impaired CaM-dependent RyR2 inhibition. Here, we investigated the RyR2 inhibitory action of the CaM p.Phe142Leu mutation (F142L; numbered including the start-Met), which markedly reduces CaM Ca2+ binding.Arrhythmogenic Calmodulin Mutations Affect the Activation and Termination of Cardiac Ryanodine Receptor-mediated Ca2+ Release
Background: Mutations in the Ca2+ sensing protein calmodulin (CaM) cause lethal cardiac arrhythmias.Results: CaM mutations impair the activation and termination of store overload-induced Ca2+ release via the cardiac ryanodine receptor (RyR2).Conclusion: CaM mutations alter RyR2-CaM interaction, thereby affecting RyR2-mediated Ca2+ release.Significance: Aberrant regulation of RyR2 store Ca2+ sensing is a potential component of calmodulin-mediated cardiac arrhythmias.Roles of the NH2-terminal Domains of Cardiac Ryanodine Receptor in Ca2+ Release Activation and Termination
Background: The NH2-terminal region of cardiac ryanodine receptor (RyR2) contains three domains (A, B, and C) that harbor many disease-causing mutations.Results: Domains A, B, and C distinctively regulate the activation and termination of Ca2+ release.Conclusion: Individual NH2-terminal domains play distinct roles in RyR2 channel function.Significance: These data shed new insights into the actions of RyR2 NH2-terminal disease mutations.
