Hypertrophic cardiomyopathy mutations increase myofilament Ca2+ buffering, alter intracellular Ca2+ handling, and stimulate Ca2+ -dependent signaling

The Journal of Biological Chemistry
Paul RobinsonCharles Redwood

Abstract

Mutations in thin filament regulatory proteins that cause hypertrophic cardiomyopathy (HCM) increase myofilament Ca2+ sensitivity. Mouse models exhibit increased Ca2+ buffering and arrhythmias, and we hypothesized that these changes are primary effects of the mutations (independent of compensatory changes) and that increased Ca2+ buffering and altered Ca2+ handling contribute to HCM pathogenesis via activation of Ca2+-dependent signaling. Here, we determined the primary effects of HCM mutations on intracellular Ca2+ handling and Ca2+-dependent signaling in a model system possessing Ca2+-handling mechanisms and contractile protein isoforms closely mirroring the human environment in the absence of potentially confounding remodeling. Using adenovirus, we expressed HCM-causing variants of human troponin-T, troponin-I, and α-tropomyosin (R92Q, R145G, and D175N, respectively) in isolated guinea pig left ventricular cardiomyocytes. After 48 h, each variant had localized to the I-band and comprised ∼50% of the total protein. HCM mutations significantly lowered the Kd of Ca2+ binding, resulting in higher Ca2+ buffering of mutant cardiomyocytes. We observed increased diastolic [Ca2+] and slowed Ca2+ reuptake, coupled with a significant d...Continue Reading

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Citations

May 24, 2019·Circulation Research·Giuliana G RepettiChristine E Seidman
May 6, 2019·International Journal of Molecular Sciences·Simona GalloTiziana Crepaldi
Feb 23, 2020·American Journal of Physiology. Heart and Circulatory Physiology·Alexander J SparrowPaul Robinson
Feb 7, 2020·The Journal of Biological Chemistry·Tianxin CaoJian-Ping Jin
Apr 16, 2020·Journal of the American Heart Association·Rahana Y ParbhudayalJolanda van der Velden
Jul 4, 2020·American Journal of Physiology. Heart and Circulatory Physiology·Paul RobinsonCharles Redwood
Oct 30, 2018·Pflügers Archiv : European journal of physiology·Richard J MarszalekBeata M Wolska
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May 15, 2019·Circulation·Godfrey L Smith, David A Eisner
Jan 2, 2021·Frontiers in Physiology·Hannah E BoycottPaul Robinson
Jan 30, 2021·The Journal of General Physiology·Michael J Greenberg, Jil C Tardiff
Feb 16, 2021·Frontiers in Cell and Developmental Biology·Felipe Salazar-RamírezGerardo García-Rivas
Mar 25, 2021·Scandinavian Cardiovascular Journal : SCJ·Simon Girmai BergerMathis Korseberg Stokke
Sep 2, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Lorenzo SantiniRaffaele Coppini
Mar 12, 2021·Cardiovascular Research·Chrishan J A RamachandraDerek J Hausenloy
Apr 16, 2021·The Journal of General Physiology·Sarah R ClippingerMichael J Greenberg
May 22, 2021·Circulation Research·Yiangos PsarasChristopher N Toepfer
Jul 31, 2021·Korean Circulation Journal·Heeyoung Seok, Jin-Hee Oh
Oct 12, 2021·The Journal of Biological Chemistry·Samantha K Barrick, Michael J Greenberg

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Methods Mentioned

BETA
transfection
nuclear translocation
transgenic

Software Mentioned

GraphPad
IonOptix
Ionwizard
InStat

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