role of calcium in cpvt vs. lqts seok hwang... · hyun seok hwang, phd . florida state university ....
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Hyun Seok Hwang, PhD Florida State University
Role of Calcium in CPVT vs. LQTs
Korean Heart Rhythm Society Symposium November, 2015
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Grant Support: NIH R01 HL71670, HL88635, Knollmann AHA Scientist Development Grant, Hwang
Vanderbilt University • Bjorn Knollmann • Sabine Huke • Dmytro Kryshtal • Kaylen Chuaquico Kor • Walter J Chazin • A. George
Acknowledgements
Florida State University Cardiac Arrhythmias Lab • Hyun Seok Hwang Univ. of Newcastle, Australia
• Derek Laver
Disclosures: None
University of California, Davis • Donald M Bers
University of Minnesota • Razvan L Cornea
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• L-type Ca channel (Cav1.2) complex localized in t-tubular membrane
• RyR2 Ca release complex localized in junctional SR membrane
• Calmodulin (CaM) localized in cytosol binds to RyR2 and Cav1.2
• Ca binding to CaM on Cav1.2 inactivates Cav1.2 channels (Ca-dependent inactivation)
Dyad - Cardiac Ca release Unit
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Excitation-Contraction Coupling in Myocytes
Knollmann, Nature, 2008
Mouse-CM
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Calmodulin (CaM)
• CaM is an essential Ca signaling protein in a wide range of biological processes.
• CaM is highly conserved among different species with 148 amino acid residues.
• Humans have 3 CaM genes – CALM1, CALM2, CALM3 – encoding the identical amino acid sequence.
• CaM mutations are associated with genetic arrhythmia syndromes responsible for sudden cardiac death.
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Crotti et al. Circulation. 2013;127:1009-1017
Calmodulin (CaM)
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Calmodulin and Sudden Cardiac Death
Nyegaard et al., Mutations in calmodulin cause ventricular tachycardia and sudden cardiac death. Am J Hum Genet. 91:703–712, 2012
Crotti et al., Calmodulin mutations associated with recurrent cardiac arrest in infants.
Circulation.127:1009-1017, 2013
Autosomal dominant, clinical presentation consistent with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
Autosomal dominant, clinical presentation consistent with Long QT Syndrome (LQTS)
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CaM mutations cause different arrhythmia phenotypes in humans
Catecholaminergic polymorphic ventricular tachycardia (CPVT) CALM1-N54I
CALM1-N98S
Nyegaard et al., Am J Hum Genet. 2012. 91, 703–712
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Long QT syndrome (LQTS) CALM2-D96V
CALM1-D130G
CALM1-F142L
Crotti et al. Circulation. 2013;127:1009-1017)
CaM mutations cause different arrhythmia phenotypes in humans
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• To determine the molecular mechanism responsible for CPVT caused by CaM mutations.
• To determine why CaM mutations cause divergent arrhythmia phenotypes in humans.
Hwang HS, et. al. 2014, Circ Res.
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Differential effect of CaM mutations on C-lobe Ca binding
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Differential effect of CaM mutations on Ca waves
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Differential effect of CaM mutations on Ca waves
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Effect of CaMKII inhibition on Ca waves
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Effect of CPVT-CaMs on Ca sparks
50 nM free [Ca], 500uM EGTA
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Regulation of single RyR2 channels by CPVT-CaMs
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CPVT-CaMs exhibit a dominant activating effect on Ca waves
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CPVT-CaMs exhibit a dominant activating effect on Ca waves
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CPVT-CaMs bind with higher affinity to RyR2 channels in diastolic Ca conditions (Cardiac SR vesicles)
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Flecainide reduced spontanous Ca waves in myocytes
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LQTS-CaMs impair CaV1.2 current inactivation
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Marsman et al. JACC. 2013
F90L CaM was identified in IVF, Sudden death at 5 years of age.
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Differential effect of CaM mutations on C-lobe Ca binding
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B
F90L CaM mutations on Ca waves
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F90L CaM mutations on CaV1.2 current inactivation
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• CPVT-CaMs are dominant activators of RyR2, whereas LQTS-CaMs have no effect on RyR2.
• LQTS-CaMs drastically impair CaV1.2 current inactivation, whereas CPVT-CaMs have little or no effect on CaV1.2.
• F90L CaM (IVF) mutation shares characteristics (a overlap syndrome) with both CPVT and LQTS CaMs.
Mechanisms of CPVT and LQTS caused by CaM mutations
F90L-CaM
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Thank you,