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Scientific article
English

Endoplasmic reticulum Ca2+ measurements reveal that the cardiac ryanodine receptor mutations linked to cardiac arrhythmia and sudden death alter the threshold for store-overload-induced Ca2+ release

Contributors

Jones, Peter P.; Jiang, Dawei; Bolstad, Jeff; Hunt, Donald J.; Zhang, Lin; Demaurex, Nicolas; Chen, S R Wayne

Published in

Biochemical journal, vol. 412, no. 1, p. 171-178

Publication date

2008

Abstract

A number of RyR2 (cardiac ryanodine receptor) mutations linked to ventricular arrhythmia and sudden death are located within the last C-terminal approximately 500 amino acid residues, which is believed to constitute the ion-conducting pore and gating domain of the channel. We have previously shown that mutations located near the C-terminal end of the predicted TM (transmembrane) segment 10, the inner pore helix, can either increase or decrease the propensity for SOICR (store-overload-induced Ca2+ release), also known as spontaneous Ca2+ release. In the present study, we have characterized an RyR2 mutation, V4653F, located in the loop between the predicted TM 6 and TM 7a, using an ER (endoplasmic reticulum)-targeted Ca2+-indicator protein (D1ER). We directly demonstrated that SOICR occurs at a reduced luminal Ca2+ threshold in HEK-293 cells (human embryonic kidney cells) expressing the V4653F mutant as compared with cells expressing the RyR2 wild-type. Single-channel analyses revealed that the V4653F mutation increased the sensitivity of RyR2 to activation by luminal Ca2+. In contrast with previous reports, the V4653 mutation did not alter FKBP12.6 (FK506-binding protein 12.6 kDa; F506 is an immunosuppressant macrolide)-RyR2 interaction. Luminal Ca2+ measurements also showed that the mutations R176Q/T2504M, S2246L and Q4201R, located in different regions of the channel, reduced the threshold for SOICR, whereas the A4860G mutation, located within the inner pore helix, increased the SOICR threshold. We conclude that the cytosolic loop between TM 6 and TM 7a plays an important role in determining the SOICR threshold and that the alteration of the threshold for SOICR is a common mechanism for RyR2-associated ventricular arrhythmia.

Keywords

  • Arrhythmias, Cardiac/*genetics/metabolism
  • Biological Transport/genetics
  • Calcium/*analysis/*metabolism
  • Cells, Cultured
  • Death, Sudden, Cardiac/*etiology
  • Endoplasmic Reticulum/*chemistry/metabolism
  • Humans
  • Myocardium/metabolism
  • Point Mutation/physiology
  • Protein Binding
  • Protein Isoforms/metabolism
  • Ryanodine Receptor Calcium Release Channel/*genetics/metabolism
  • Tacrolimus Binding Protein 1A/metabolism

UNIGE affiliation entities

UNIGE research groups

Citation (ISO format)

JONES, Peter P. et al. Endoplasmic reticulum Ca2+ measurements reveal that the cardiac ryanodine receptor mutations linked to cardiac arrhythmia and sudden death alter the threshold for store-overload-induced Ca2+ release. In: Biochemical journal, 2008, vol. 412, n° 1, p. 171–178. doi: 10.1042/BJ20071287

Main files (1)

Article

Identifiers

Additional URL for this publication

http://www.biochemj.org/bj/412/0171/4120171.pdf

Journal ISSN

0264-6021
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Technical informations

Creation

27/03/2012 09:23:13

First validation

27/03/2012 09:23:13

Update

14/03/2023 17:20:06

Status update

14/03/2023 17:20:06

Last indexation

29/10/2024 19:11:49
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