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Disparities in the association of the ryanodine receptor and the FK506-binding proteins in mammalian heart

Zissimopoulos, Spyros, Seifan, Sara, Maxwell, Chloe, Williams, Alan John and Lai, Francis Anthony 2012. Disparities in the association of the ryanodine receptor and the FK506-binding proteins in mammalian heart. Journal of Cell Science 125 (7) , pp. 1759-1769. 10.1242/jcs.098012

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The FK506-binding proteins (FKBP12 and FKBP12.6; also known as FKBP1A and FKBP1B, respectively) are accessory subunits of the ryanodine receptor (RyR) Ca2+ release channel. Aberrant RyR2–FKBP12.6 interactions have been proposed to be the underlying cause of channel dysfunction in acquired and inherited cardiac disease. However, the stoichiometry of the RyR2 association with FKBP12 or FKBP12.6 in mammalian heart is currently unknown. Here, we describe detailed quantitative analysis of cardiac stoichiometry between RyR2 and FKBP12 or FKBP12.6 using immunoblotting and [3H]ryanodine-binding assays, revealing striking disparities between four mammalian species. In mouse and pig heart, RyR2 is found complexed with both FKBP12 and FKBP12.6, although the former is the most abundant isoform. In rat heart, RyR2 is predominantly associated with FKBP12.6, whereas in rabbit it is associated with FKBP12 only. Co-immunoprecipitation experiments demonstrate RyR2-specific interaction with both FKBP isoforms in native cardiac tissue. Assuming four FKBP-binding sites per RyR2 tetramer, only a small proportion of available sites are occupied by endogenous FKBP12.6. FKBP interactions with RyR2 are very strong and resistant to drug (FK506, rapamycin and cyclic ADPribose) and redox (H2O2 and diamide) treatment. By contrast, the RyR1–FKBP12 association in skeletal muscle is readily disrupted under oxidative conditions. This is the first study to directly assess association of endogenous FKBP12 and FKBP12.6 with RyR2 in native cardiac tissue. Our results challenge the widespread perception that RyR2 associates exclusively with FKBP12.6 to near saturation, with important implications for the role of the FK506-binding proteins in RyR2 pathophysiology and cardiac disease.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QH Natural history > QH301 Biology
Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine
Uncontrolled Keywords: Ryanodine receptor; FK506-binding protein; Cardiac muscle; Heart failure; Arrhythmias
Publisher: The Company of Biologists
ISSN: 0021-9533
Last Modified: 27 Mar 2020 02:38

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