1999 Fiscal Year Final Research Report Summary
Specific interaction of FK506 binding protein (FKBP) isoforms with the ryanodine/CaィイD12+ィエD1 release channel subtypes
| Project/Area Number |
10470024
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
ITO Yushi Kyushu University, Graduate School of Medical Sciences, Professor, 大学院・医学系研究科, 教授 (80037506)
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| Co-Investigator(Kenkyū-buntansha) |
OIKE Masahiro Kyushu University, Graduate School of Medical Sciences, Lecturer, 大学院・医学系研究科, 講師 (70271103)
INOUE Ryuji Kyushu University, Graduate School of Medical Sciences, Associate Professor, 大学院・医学系研究科, 助教授 (30232573)
ONOUE Hitoshi Kyushu University, Graduate School of Medical Sciences, Lecturer, 大学院・医学系研究科, 講師 (70221166)
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| Project Period (FY) |
1998 – 1999
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| Keywords | CaィイD12+ィエD1 / ryanodine receptor / FK506 binding protein / isoform / subtype / cardiac muscle / skeletal muscle |
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| Research Abstract |
The calcium release channels (CRC)/ryanodine receptor of skeletal (Sk) and (C) muscle sarcoplasmic reticulum (SR) are hetero-oligomeric complexes with the structural formulas (ryanodine receptor(RYR)1 receptor)ィイD24ィエD2 (FKBP12)ィイD24ィエD2 and (RYP2 protomer)ィイD24ィエD2 (FKBP12.6)ィイD24ィエD2, respectively, where FKBP12 and FKBP12.6 are isoforms of the 12-kDa receptor for the immunosuppressant drug FK506. Using ィイD135ィエD1S-labeled FKBP12 and ィイD135ィエD1S-labeled FKBP12.6 as probes to study the interaction with CRC, we find that : 1) analogous to its action in skeletal muscle sarcoplasmic reticulum (SkMSR), FK506 dissociates FKBP12.6 from CSR ; 2) both FKBP isoforms bind to FKBP-stripped SkMSR and exchange with endogenously bound FKBP12 of SkMSR ; and 3) by contrast, only FKBP12.6 exchanges with endogenously bound FKBP12.6 or rebinds to FKBP-stripped CSR. This selective binding appears to explain why the cardiac CRC is isolated as a complex with FKBP12.6, whereas the skeletal muscle CRC is isolated as a complex with FKBP12.6 although only FKBP12 is detectable in the myoplasm of both muscle types. In contrast to the activation of the channel by removal of FKBP from skeletal muscle, no activation is detected in CRC activity in FKBP-stripped CSR. This deferential action of FKBP may reflect a fundamental difference in the modulation of excitation-contraction coupling in heart versus skeletal muscle.
we also examined whether FKBP is associated with the RYR in situ by immunolocalization studies. In rat skeletal muscle section, both the RYR and FKBP were detected as transverse bands with periodicity along the full length of the muscle fiber. When the same section was dual-proved with anti-RYR and anti-FKBP antibody, the bands of FKBP superimposed upon the bands of the RYR. These results suggest that FKBP is associated with the RYR in situ and modulates the function of the RYR/CRC in skeletal muscle.
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Research Products
(2 results)
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[Publications] Onoue, H., Tanaka, H., Tanaka, K., Doira N., Ito, Y.: "Heterooligomer of type membrane fraction 1, 4, 5-triphosphate receptor expressed in rat liver membrane fraction exists as tetrameric complex"Biochem. Biophys. Res. Commun.. 267(3). 928-933 (2000)
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