Interaction of levosimendan with cadiac troponin C in the presence of cardiac troponin I peptides.
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/128100
- author
- Sorsa, T ; Pollesello, P ; Permi, P ; Drakenberg, Torbjörn LU and Kilpeläinen, I
- organization
- publishing date
- 2003
- 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
- 2016-04-01 17:01:36
- date last changed
- 2022-01-28 23:50:12
@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}},
doi = {{10.1016/S0022-2828(03)00178-0}},
volume = {{35}},
year = {{2003}},
}