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The 12 kDa FK506-binding protein, FKBP12, modulates the Ca(2+)-flux properties of the type-3 ryanodine receptor.

Abstract：

:We have characterised the functional regulation of the type-3 ryanodine receptor by the 12 kDa FK506-binding protein. Wild-type type-3 ryanodine receptor and mutant type-3 ryanodine receptor in which the critical valine at position 2322 in the central 12 kDa FK506-binding protein binding site was substituted by aspartate, were stably expressed in human embryonic kidney cells. In contrast to the wild-type receptor, the mutant receptor was strongly impaired in binding to immobilised glutathione S-transferase 12 kDa FK506-binding protein. Caffeine-induced 45Ca(2+)-efflux was markedly increased in cells expressing mutant type-3 ryanodine receptor whereas the maximal-releasable Ca2+ was not affected. Confocal Ca2+ imaging provided clear evidence for a much higher sensitivity of the mutant receptor, which showed global Ca2+ release at about 20-fold lower caffeine concentrations than the wild-type receptor. Spontaneous Ca2+ sparks were observed in both wild-type- and mutant-expressing cells but the number of sparking cells was about 1.5-fold higher in the mutant group, suggesting that the degree of FK506 binding controls the stability of the closed state of ryanodine receptor channels. Furthermore, overexpression of 12 kDa FK506-binding protein decreased the number of sparking cells in the wild-type-expressing cells whereas it did not affect the number of sparking cells in cells expressing the mutant receptor. Concerning spark properties, the amplitude and duration of Ca2+ sparks mediated by mutant channels were significantly reduced in comparison to wild-type channels. This suggests that functional coupling between different mutant type-3 ryanodine receptor channels in a cluster is impaired. Our findings show for the first time that the central binding site for the 12 kDa FK506-binding protein of type-3 ryanodine receptor, encompassing the critical valine proline motif, plays a crucial role in the modulation of the Ca2+ release properties of the type-3 ryanodine receptor channel, including the regulation of both global Ca2+ responses and spontaneous Ca2+ sparks.

journal_name

J Cell Sci

journal_title

Journal of cell science

authors

Van Acker K,Bultynck G,Rossi D,Sorrentino V,Boens N,Missiaen L,De Smedt H,Parys JB,Callewaert G

doi

10.1242/jcs.00948

keywords:

subject

Has Abstract

pub_date

2004-03-01 00:00:00

pages

1129-37

issue

Pt 7

eissn

0021-9533

issn

1477-9137

pii

jcs.00948

journal_volume

117

pub_type

杂志文章

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The 12 kDa FK506-binding protein, FKBP12, modulates the Ca(2+)-flux properties of the type-3 ryanodine receptor.