期刊
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES
卷 378, 期 1879, 页码 -出版社
ROYAL SOC
DOI: 10.1098/rstb.2022.0169
关键词
ryanodine receptor; FKBP12; 6; sarcoplasmic reticulum; Ca2+ release
类别
Cardiac ryanodine receptors (RyR2) play a crucial role in releasing intracellular calcium essential for cardiac myocyte contraction. The regulation of ion channel opening by intracellular factors, including FK506 binding proteins FKBP12 and FKBP12.6, and their impact on RyR2 activity and cardiac contraction are still debated. This study demonstrates that FKBP12 activates RyR2 with high affinity and inhibits RyR2 with lower affinity, suggesting a model of negative cooperativity in FKBP12 binding. The dissociation of FKBP12/12.6 could dynamically affect RyR2 activity, indicating the significant role of FKBP12/12.6 in Ca2+ signaling and cardiac function.
Cardiac ryanodine receptors (RyR2) release the Ca2+ from intracellular stores that is essential for cardiac myocyte contraction. The ion channel opening is tightly regulated by intracellular factors, including the FK506 binding proteins, FKBP12 and FKBP12.6. The impact of these proteins on RyR2 activity and cardiac contraction is debated, with often apparently contradictory experimental results, particularly for FKBP12. The isoform that regulates RyR2 has generally been considered to be FKBP12.6, despite the fact that FKBP12 is the major isoform associated with RyR2 in some species and is bound in similar proportions to FKBP12.6 in others, including sheep and humans. Here, we show time- and concentration-dependent effects of adding FKBP12 to RyR2 channels that were partly depleted of FKBP12/12.6 during isolation. The added FKBP12 displaced most remaining endogenous FKBP12/12.6. The results suggest that FKBP12 activates RyR2 with high affinity and inhibits RyR2 with lower affinity, consistent with a model of negative cooperativity in FKBP12 binding to each of the four subunits in the RyR tetramer. The easy dissociation of some FKBP12/12.6 could dynamically alter RyR2 activity in response to changes in in vivo regulatory factors, indicating a significant role for FKBP12/12.6 in Ca2+ signalling and cardiac function in healthy and diseased hearts.This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.
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