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In situ modulation of the human cardiac ryanodine receptor (hRyR2) by FKBP12.6

George, Christopher, Sorathia, Rina, Bertrand, Benedicte M. A. and Lai, Francis Anthony 2003. In situ modulation of the human cardiac ryanodine receptor (hRyR2) by FKBP12.6. Biochemical Journal 370 (2) , pp. 579-589. 10.1042/BJ20021433

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The ryanodine receptor complex (RyR), a large oligomeric assembly that functions as a Ca2+-release channel in the sarcoplasmic reticulum (SR)/endoplasmic reticulum (ER), comprises four RyR subunits and four FK506-binding proteins (FKBP). The precise mode of interaction and modulation of the cardiac RyR (RyR2) channel by FKBP12/FKBP12.6 remains to be fully defined. We have generated a series of Chinese-hamster ovary (CHO) cell lines stably expressing discrete levels of recombinant human RyR2 (hRyR2) (CHOhRyR2). Confocal microscopy of CHOhRyR2 cells co-expressing either FKBP12 or FKBP12.6 demonstrated that FKBP12.6 was sequestered from the cytoplasm to ER membranes as the cellular levels of hRyR2 increased. There was negligible hRyR2-induced subcellular redistribution of FKBP12. The magnitude of Ca2+ release in CHOhRyR2 cells in response to stimulation by 4-chloro-m-cresol was in direct proportion to the expression levels of hRyR2. However, in CHOhRyR2 cells co-expressing FKBP12.6, Ca2+ release triggered by the addition of 4-chloro-m-cresol was markedly decreased. In contrast, co-expression of FKBP12 did not affect agonist-induced Ca2+ release in CHOhRyR2 cells. Resting cytoplasmic [Ca2+] in CHOhRyR2 remained unaltered after co-expression of FKBP12 or FKBP12.6, but estimation of the ER Ca2+ load status showed that co-expression of FKBP12.6, but not FKBP12, promoted superfilling of the ER Ca2+ store which could not be released by RyR2 after agonist activation. The effects of FKBP12.6 on hRyR2-mediated intracellular Ca2+ handling could be antagonized using rapamycin (5µM). These results suggest that FKBP12.6 associates with hRyR2 in situ to modulate precisely the functionality of hRyR2 Ca2+-release channel.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Uncontrolled Keywords: channel regulation ; FK506-binding protein ; intracellular Ca2+ homoeostasis ; ryanodine receptor.
Publisher: Biochemical Society
ISSN: 0264-6021
Last Modified: 27 Mar 2020 02:38

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