The calsequestrin mutation CASQ2D307H does not affect protein stability and targeting to the junctional sarcoplasmic reticulum but compromises its dynamic regulation of calcium buffering.

The Journal of Biological Chemistry
Anuradha KalyanasundaramMuthu Periasamy

Abstract

Mutations in cardiac ryanodine receptor (RYR2) and cardiac calsequestrin (CASQ2) genes are linked to catecholaminergic polymorphic ventricular tachycardia, a life-threatening genetic disease. They predispose young individuals to cardiac arrhythmia in the absence of structural abnormalities. One such mutation that changes an aspartic residue to histidine at position 307 in CASQ2 has been linked to catecholaminergic polymorphic ventricular tachycardia. In this study we made a transgenic mouse model expressing the mutant CASQ2(D307H) protein in a CASQ2 null background and investigated if the disease is caused by accelerated degradation of the mutant protein. Our data suggest that the mutant protein can be expressed, is relatively stable, and targets appropriately to the junctional sarcoplasmic reticulum. Moreover, it partially normalizes the ultrastructure of the sarcoplasmic reticulum, which was altered in the CASQ2 null background. In addition, overexpression of the mutant protein does not cause any pathology and/or structural changes in the myocardium. We further demonstrate, using purified protein, that the mutant protein is very stable under chemical and thermal denaturation but shows abnormal Ca(2+) buffering characteristics...Continue Reading

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Citations

Dec 16, 2011·The Journal of Biological Chemistry·Emiliano J SanchezChulHee Kang
Mar 23, 2011·Cold Spring Harbor Perspectives in Biology·Daniel Prins, Marek Michalak
Oct 11, 2011·American Journal of Physiology. Heart and Circulatory Physiology·Anuradha KalyanasundaramMuthu Periasamy
Dec 27, 2011·American Journal of Physiology. Heart and Circulatory Physiology·Michela Faggioni, Björn C Knollmann
Oct 31, 2012·Cellular and Molecular Life Sciences : CMLS·Marta GaburjakovaMuthu Periasamy
Feb 16, 2011·Biophysical Journal·Maura PortaMichael Fill
Feb 2, 2013·Journal of Molecular and Cellular Cardiology·Dirk Gillespie, Michael Fill
Jan 27, 2011·The Biochemical Journal·Naresh C BalMuthu Periasamy
May 15, 2013·Experimental Cell Research·Carmelina ChiarelloPompeo Volpe
Nov 5, 2011·Journal of Cellular and Molecular Medicine·Atara NovakOfer Binah
Jun 27, 2012·Nature Reviews. Cardiology·Luigi VenetucciSilvia G Priori
Apr 23, 2020·Cardiovascular Research·Vassilios J BezzeridesWilliam T Pu
Jun 4, 2020·Journal of Muscle Research and Cell Motility·Daniela RossiVincenzo Sorrentino
Jun 24, 2020·Cell Calcium·Qian Wang, Marek Michalak
Aug 29, 2019·ACS Omega·Harapriya ChakravartyAshoke Sharon

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