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Differential Ca2+ sensitivity of RyR2 mutations reveals distinct mechanisms of channel dysfunction in sudden cardiac death

Thomas, Nia Lowri, Lai, Francis Anthony and George, Christopher H. 2005. Differential Ca2+ sensitivity of RyR2 mutations reveals distinct mechanisms of channel dysfunction in sudden cardiac death. Biochemical and Biophysical Research Communications 331 (1) , pp. 231-238. 10.1016/j.bbrc.2005.02.194

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Abstract

Arrhythmogenic point mutations in RyR2 result in abnormal Ca2+ release following cardiac stimulation, leading to sudden cardiac death (SCD). Recently, we have demonstrated that significant functional differences exist between SCD-linked RyR2 mutations. Here, we investigated the molecular basis of this heterogeneity and determined the sensitivity of mutant RyR2 channels to cytoplasmic [Ca2+] ([Ca2+]c) in living cells. Using streptolysin-O permeabilised human embryonic kidney cells, [Ca2+]c was clamped in cells expressing GFP-tagged wild-type (WT) or SCD-linked RyR2 mutants (L433P, N2386I, and R176Q/T2504M). Although resting [Ca2+]c was comparable in all cells, RyR2 mutants were characterised by a profound loss of Ca2+-dependent inhibition following caffeine stimulation when compared with WT channels. The ER Ca2+ store was not perturbed in these experiments. Our findings support the hypothesis that SCD-linked mutational loci may be an important mechanistic determinant of RyR2 dysfunction and indicate that there is unlikely to be a unifying mechanism for channel dysfunction in SCD.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: Elsevier
ISSN: 0006-291X
Last Modified: 27 Mar 2020 02:39
URI: http://orca-mwe.cf.ac.uk/id/eprint/68878

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