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Preclinical Cardiac Electrophysiology Assessment by Dual Voltage and Calcium Optical Mapping of Human Organotypic Cardiac Slices
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Arrhythmia mutations in calmodulin cause conformational changes that affect interactions with the cardiac

Kaiqian Wang1, Christian Holt2, Jocelyn Lu1

  • 1Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.

Proceedings of the National Academy of Sciences of the United States of America
|October 24, 2018
PubMed

Insights

Calmodulin mutations linked to long-QT syndrome cause distinct structural changes, altering interactions with the cardiac calcium channel. These findings reveal diverse mechanisms behind cardiac arrhythmia caused by calmodulin disease mutations.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Cardiology

Background:

  • Calmodulin (CaM) is a highly conserved eukaryotic protein regulating over 100 targets.
  • Mutations in the CALM gene are linked to severe cardiac arrhythmia syndromes, including long-QT syndrome.
  • Previous studies showed CaM mutations affect cardiac ion channels, but lacked direct structural evidence.

Purpose of the Study:

  • To provide direct structural insights into disease-associated calmodulin mutations.
  • To investigate the structural basis of how CaM mutations affect the cardiac voltage-gated calcium channel (CaV1.2).

Main Methods:

  • Crystallography
  • Nuclear Magnetic Resonance (NMR) spectroscopy
  • Structural investigation of CaM mutants complexed with the CaV1.2 IQ domain.

Main Results:

  • Two mutants (D95V, N97I) induced significant C-terminal lobe distortion, creating novel pathological conformations and altering CaV1.2 IQ domain interactions.
  • The N97S mutation reduced Ca2+ affinity by straining EF hand 3.
  • The F141L mutation, in its Ca2+-free state, exhibited structural changes that enhanced CaV1.2 IQ domain affinity.

Conclusions:

  • Different CaM disease mutations employ distinct structural mechanisms to disrupt Ca2+-dependent inactivation of CaV1.2.
  • These findings elucidate the molecular basis of calmodulinopathies and cardiac arrhythmias.
  • Structural insights are crucial for understanding and potentially treating CaM-related cardiac disorders.
Keywords:
NMRX-ray crystallographycalcium channelscalcium signalinginactivation

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