1999 Fiscal Year Final Research Report Summary
Study on chronic heart failure using mutant phospholamban transgenic mice
| Project/Area Number |
10670662
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Yamaguchi University |
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Principal Investigator |
KIMURA Yoshihiro Yamaguchi University School of Medicine, Assistant professor, 医学部, 教授 (90301308)
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| Co-Investigator(Kenkyū-buntansha) |
YAMADA Yasue Yamaguchi University School of Medicine, Research associate, 医学部, 助手 (00166737)
INUI Makoto Yamaguchi University School of Medicine, Professor, 医学部, 教授 (70223237)
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| Project Period (FY) |
1998 – 1999
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| Keywords | cardiac sarcoplasmic reticulum / calcium ATPase / phospholamban / heart failure / transgenic mice |
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| Research Abstract |
Phospholamban (PLN), an integral membrane protein of cardiac sarcoplasmic reticulum, reversibly inhibits the CaィイD12+ィエD1-ATPase (SERCA) to play a pivotal role in the regulation of cardiac contractility and relaxation. We examined the molecular mechanism of SERCA inhibition by PLN and we have created transgenic mice in which the dominant, highly inhibitory PLN mutant proteins are overexpressed in collaboration with Dr. D. H. MacLennan of the University of Toronto. Our results are following :
1. PLN interacts with SERCA through at least two, possibly three sites ; cytoplasmic domain (domain Ia), transmembrane helix (domain II), and cytoplasmic-membrane boundary (domain Ib). Intramembrane interactions are inhibitory on SERCA activity, while the cytoplasmic interactions are not inhibitory itself although it is essential for the physiological regulatory effect. We propose that PLN and SERCA interact via a four base circuit through which long range inhibitory interactions night be propagated among a series of cytoplasmic and transmembrane interaction sites.
2. PLN transmembrane domain interacts with the transmembrane sequence (M6) of SERCA. The interaction site consists of four residues which form the hydrophobic face of the proposed helix on the opposite face to the CaィイD12+ィエD1 binding site. As M& is located in a shallow groove with the key residues which form the proposed interaction site facing the lipid bilayer, it is conceivable that the groove may provide the PLN transmembrane helix with access to the interaction site.
3. Transgenic mice overexpressing monomeric, dominant-acting, highly inhibitory PLN mutants were generated. They exhibited impaired cardiac contractility and relaxation.
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Research Products
(12 results)
