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Interaction of levosimendan with cadiac troponin C in the presence of cardiac troponin I peptides.

Sorsa, T; Pollesello, P; Permi, P; Drakenberg, Torbjörn LU and Kilpeläinen, I (2003) In Journal of Molecular and Cellular Cardiology 35(9). p.1055-1061
Abstract
The interaction between troponin C (TnC) and troponin I (TnI) is essential for the regulation of muscle contraction. There are several binding sites for TnI on TnC that are differentially occupied depending on the phase of the contraction/relaxation cycle. TnI and TnC interact in an antiparallel fashion with each other. The C-domain of cTnC and the N-domain region of cTnI(residues 33–70) always interact under physiological conditions, whereas the interaction between regulatory regions of TnC and TnI (residues 128–166) is calcium dependent. Previously, it has been shown that levosimendan, a calcium sensitizer used as a treatment for acute heart failure, can interact with both domains of isolated cTnC. To understand which interaction is... (More)
The interaction between troponin C (TnC) and troponin I (TnI) is essential for the regulation of muscle contraction. There are several binding sites for TnI on TnC that are differentially occupied depending on the phase of the contraction/relaxation cycle. TnI and TnC interact in an antiparallel fashion with each other. The C-domain of cTnC and the N-domain region of cTnI(residues 33–70) always interact under physiological conditions, whereas the interaction between regulatory regions of TnC and TnI (residues 128–166) is calcium dependent. Previously, it has been shown that levosimendan, a calcium sensitizer used as a treatment for acute heart failure, can interact with both domains of isolated cTnC. To understand which interaction is relevant for the mechanism of calcium sensitization, we used a more complete troponin model obtained by complexing cTnI32–79 and cTnI128–180 with calcium-saturated cTnCCS. The cTnI peptides bound to cTnCCS to form a 1:1:1 complex. The interaction of levosimendan with this complex was followed by 1H–15N heteronuclear correlation spectroscopy. It was clear that based on chemical shift changes, cTnI32–79 blocked the levosimendan interaction sites on the C-domain, whereas cTnI128–180 did not compete with levosimendan for the binding site on the N-domain. Hence, the effective binding site of levosimendan on cTnC resulting in the calcium-sensitizing effect is located in the regulatory domain (N-domain). (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Molecular and Cellular Cardiology
volume
35
issue
9
pages
1055 - 1061
publisher
Elsevier
external identifiers
  • wos:000185494800009
  • pmid:12967628
  • scopus:0043142324
ISSN
1095-8584
DOI
10.1016/S0022-2828(03)00178-0
language
English
LU publication?
yes
id
a493e77c-758e-47da-a509-b828ac060349 (old id 128100)
date added to LUP
2007-06-29 14:27:40
date last changed
2018-01-07 09:42:12
@article{a493e77c-758e-47da-a509-b828ac060349,
  abstract     = {The interaction between troponin C (TnC) and troponin I (TnI) is essential for the regulation of muscle contraction. There are several binding sites for TnI on TnC that are differentially occupied depending on the phase of the contraction/relaxation cycle. TnI and TnC interact in an antiparallel fashion with each other. The C-domain of cTnC and the N-domain region of cTnI(residues 33–70) always interact under physiological conditions, whereas the interaction between regulatory regions of TnC and TnI (residues 128–166) is calcium dependent. Previously, it has been shown that levosimendan, a calcium sensitizer used as a treatment for acute heart failure, can interact with both domains of isolated cTnC. To understand which interaction is relevant for the mechanism of calcium sensitization, we used a more complete troponin model obtained by complexing cTnI32–79 and cTnI128–180 with calcium-saturated cTnCCS. The cTnI peptides bound to cTnCCS to form a 1:1:1 complex. The interaction of levosimendan with this complex was followed by 1H–15N heteronuclear correlation spectroscopy. It was clear that based on chemical shift changes, cTnI32–79 blocked the levosimendan interaction sites on the C-domain, whereas cTnI128–180 did not compete with levosimendan for the binding site on the N-domain. Hence, the effective binding site of levosimendan on cTnC resulting in the calcium-sensitizing effect is located in the regulatory domain (N-domain).},
  author       = {Sorsa, T and Pollesello, P and Permi, P and Drakenberg, Torbjörn and Kilpeläinen, I},
  issn         = {1095-8584},
  language     = {eng},
  number       = {9},
  pages        = {1055--1061},
  publisher    = {Elsevier},
  series       = {Journal of Molecular and Cellular Cardiology},
  title        = {Interaction of levosimendan with cadiac troponin C in the presence of cardiac troponin I peptides.},
  url          = {http://dx.doi.org/10.1016/S0022-2828(03)00178-0},
  volume       = {35},
  year         = {2003},
}