Different arrhythmia-associated calmodulin mutations have distinct effects on cardiac SK channel regulation.

The Journal of General Physiology
Hannah A LedfordNipavan Chiamvimonvat

Abstract

Calmodulin (CaM) plays a critical role in intracellular signaling and regulation of Ca2+-dependent proteins and ion channels. Mutations in CaM cause life-threatening cardiac arrhythmias. Among the known CaM targets, small-conductance Ca2+-activated K+ (SK) channels are unique, since they are gated solely by beat-to-beat changes in intracellular Ca2+. However, the molecular mechanisms of how CaM mutations may affect the function of SK channels remain incompletely understood. To address the structural and functional effects of these mutations, we introduced prototypical human CaM mutations in human induced pluripotent stem cell-derived cardiomyocyte-like cells (hiPSC-CMs). Using structural modeling and molecular dynamics simulation, we demonstrate that human calmodulinopathy-associated CaM mutations disrupt cardiac SK channel function via distinct mechanisms. CaMD96V and CaMD130G mutants reduce SK currents through a dominant-negative fashion. By contrast, specific mutations replacing phenylalanine with leucine result in conformational changes that affect helix packing in the C-lobe, which disengage the interactions between apo-CaM and the CaM-binding domain of SK channels. Distinct mutant CaMs may result in a significant reductio...Continue Reading

References

May 2, 1985·Nature·Y S BabuW J Cook
Feb 15, 1984·European Journal of Biochemistry·R E KlevitR J Williams
Jan 1, 1995·Annual Review of Biophysics and Biomolecular Structure·A Crivici, M Ikura
Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Oct 23, 1997·Proceedings of the National Academy of Sciences of the United States of America·T M IshiiJ Maylie
Oct 6, 1997·Proceedings of the National Academy of Sciences of the United States of America·W J JoinerL K Kaczmarek
Aug 4, 1998·Current Opinion in Neurobiology·C VergaraJ P Adelman
Jul 8, 2000·Trends in Cell Biology·D Chin, A R Means
Feb 5, 2002·Annual Review of Physiology·Yoshiro Saimi, Ching Kung
Mar 7, 2002·Lancet·Michel HaïssaguerreJacques Clémenty
Sep 19, 2003·The Journal of Biological Chemistry·Yanfang XuNipavan Chiamvimonvat
Apr 6, 2004·Methods in Enzymology·Carol A RohlDavid Baker
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Aug 2, 2005·American Journal of Physiology. Heart and Circulatory Physiology·Dipika TutejaNipavan Chiamvimonvat
Oct 14, 2005·Journal of Computational Chemistry·James C PhillipsKlaus Schulten
Dec 24, 2005·Proteins·Vladimir Yarov-YarovoyDavid Baker
Nov 18, 2006·Circulation Research·Ling LuNipavan Chiamvimonvat
Sep 11, 2007·Journal of Molecular Biology·Chu WangDavid Baker
Dec 22, 2007·Circulation Research·Qian ZhangNipavan Chiamvimonvat
Mar 21, 2008·Journal of Computational Chemistry·Sunhwan JoWonpil Im
May 16, 2009·Journal of Computational Chemistry·B R BrooksM Karplus
Oct 10, 2009·Proceedings of the National Academy of Sciences of the United States of America·Ling LuNipavan Chiamvimonvat
Oct 23, 2010·The Journal of Biological Chemistry·Hyo Jeong KimEbenezer N Yamoah
Dec 14, 2011·Proceedings of the National Academy of Sciences of the United States of America·Vladimir Yarov-YarovoyWilliam A Catterall
Oct 9, 2012·American Journal of Human Genetics·Mette NyegaardAnders D Børglum
Feb 8, 2013·Circulation·Lia CrottiAlfred L George
Mar 26, 2013·Journal of the American Heart Association·Po-Cheng ChangTomohiko Ai
Apr 24, 2014·Biochemical and Biophysical Research Communications·Masakazu FukudaMasafumi Yano
Jun 22, 2014·Proceedings of the National Academy of Sciences of the United States of America·Sassan RafizadehNipavan Chiamvimonvat
Dec 3, 2014·Heart Rhythm : the Official Journal of the Heart Rhythm Society·Griffin J ReedMichael J Ackerman

❮ Previous
Next ❯

Citations

Feb 25, 2021·Pflügers Archiv : European journal of physiology·Xiao-Dong ZhangNipavan Chiamvimonvat

❮ Previous
Next ❯

Software Mentioned

- GUI
pClamp
Maxchelator
Visual Molecular Dynamics
Chimera
NAMD
Origin
OriginLab
Rosetta relax
GraphPad Prism

Related Concepts

Related Feeds

Atrial Fibrillation

Atrial fibrillation is a common arrhythmia that is associated with substantial morbidity and mortality, particularly due to stroke and thromboembolism. Here is the latest research.

Cardiovascular Homeostasis

Cardiovascular regulation and homeostasis is important in maintaining health and dysfunction may lead to cardiovascular diseases. Nitric oxide and vascular endothelium are one of many molecules involved in the homeostatic mechanism. Here is the latest research on cardiovascular homeostasis.

Adhesion Molecules in Health and Disease

Cell adhesion molecules are a subset of cell adhesion proteins located on the cell surface involved in binding with other cells or with the extracellular matrix in the process called cell adhesion. In essence, cell adhesion molecules help cells stick to each other and to their surroundings. Cell adhesion is a crucial component in maintaining tissue structure and function. Discover the latest research on adhesion molecule and their role in health and disease here.

Arrhythmia

Arrhythmias are abnormalities in heart rhythms, which can be either too fast or too slow. They can result from abnormalities of the initiation of an impulse or impulse conduction or a combination of both. Here is the latest research on arrhythmias.

Related Papers

Pflügers Archiv : European journal of physiology
Xiao-Dong ZhangNipavan Chiamvimonvat
Heart Rhythm : the Official Journal of the Heart Rhythm Society
Xiao-Dong ZhangNipavan Chiamvimonvat
© 2021 Meta ULC. All rights reserved