Details

Autor(en) / Beteiligte

• Yan-Ting Zhao
• Yun-Bo Guo
• Xue-Xin Fan
• Hua-Qian Yang
• Peng Zhou
• Zheng Chen
• Qi Yuan
• Haihong Ye
• Guang-Ju Ji
• Shi-Qiang Wang

Titel

Role of FK506-binding protein in Ca^2＋ spark regulation

Ist Teil von

• 科学通报：英文版, 2017, Vol.62 (19), p.1295-1303

Erscheinungsjahr

2017

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• The elementary Ca^2＋ release events, Ca2＋ sparks, has been found for a quarter of century. However, the molecular regulation of the spark generator, the ryanodine receptor （RyR） on the sarcoplasmic reticulum, remains obscure. Although each subunit of the RyR homotetramer has a site for FKS06-binding protein （FKBP）, the role of FKBPs in modifying RyR Ca^2＋ sparks has been debated for long. One of the reasons behind the controversy is that most previous studies detect spontaneous sparks, where the mixture with out-of-focus events and local wavelets prevents an accurate characterization of Ca^2＋ sparks. In the pre- sent study, we detected Ca^2＋ sparks triggered by single L-type Ca^2＋ channels （LCCs） under loose-seal patch clamp conditions in FKS06-treated or FKBPI2.6 knockout cardiomyocytes. We found that FKBP dissociation both by FKS06 and by rapamycin decreased the Ca^2＋ spark amplitude in ventricular cardiomyocytes. This change was neither due to decreased releasable Ca^2＋ in the sarcoplasmic reticulum, nor explained by changed RyR sensitivity. Actually FKS06 increased the LCC-RyR coupling probability and curtailed the latency for an LCC to trigger a RyR Ca^2＋ spark. FKBP12.6 knockout had similar effects as FKS06/rapamycin treatment, indicating that the decreased spark amplitude was attributable to the dissociation of FKBP12.6 rather than FKBP12. We also explained how decreased amplitude of spontaneous sparks after FKBP dissociation sometimes appears to be increased or unchanged due to inappropriate data processing. Our results provided firm evidence that without the inter-RyR coordination by functional FKBP12.6, the RyR recruitment during a Ca^2＋ spark would be compromised despite the sensitization of individual RyRs.