TY - JOUR
T1 - The role of the CA2+ regulatory sites of skeletal troponin C in modulating muscle fibre reactivity to the CA2+ sensitizer bepridil
AU - Kischel, P.
AU - Bastide, B.
AU - Potter, J. D.
AU - Mounier, Y.
N1 - Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2000
Y1 - 2000
N2 - 1. The Ca 2+ -sensor protein troponin C (TnC) exerts a key role in the regulation of muscle contraction, and constitutes a target for Ca 2+ sensitizer compounds, such as bepridil, known to increase its apparent Ca 2+ affinity. Moreover, bepridil has been reported to exert a differential effect in slow and fast skeletal muscle fibres, which express the slow/cardiac and fast TnC isoform, respectively. 2. The role of the TnC isoform in establishing the differential effect of bepridil was assessed in slow soleus and fast tibialis rat skinned fibres, by extraction of endogenous TnC and consecutive reconstitution with either slow or fast recombinant TnC. A mutant (VG2), lacking the regulatory site II, was also used to distinguish the role of each regulatory site. 3. Fast tibialis fibres reconstituted with cardiac TnC exhibited a typical slow bepridil reactivity, while slow soleus fibres reincorporated with fast TnC displayed a typically fast reactivity to bepridil. These results indicated that the differential effect of bepridil in slow and fast fibres is related to the TnC isoform predominantly expressed in a fibre. 4. Experiments with the VG2 mutant demonstrated that BPD can achieve an increase in the Ca 2+ affinity in the absence of a functional site II. Thus, site I was necessary for the BPD effect to be independent of the Ca 2+ concentration. Moreover, the amplitude of the reinforcement in the Ca 2+ affinity, induced by the binding of bepridil to the TnC molecule, is dependent on the number of functional regulatory sites, the larger affinity reinforcement being detected when only one regulatory site (either site I or II) is functional.
AB - 1. The Ca 2+ -sensor protein troponin C (TnC) exerts a key role in the regulation of muscle contraction, and constitutes a target for Ca 2+ sensitizer compounds, such as bepridil, known to increase its apparent Ca 2+ affinity. Moreover, bepridil has been reported to exert a differential effect in slow and fast skeletal muscle fibres, which express the slow/cardiac and fast TnC isoform, respectively. 2. The role of the TnC isoform in establishing the differential effect of bepridil was assessed in slow soleus and fast tibialis rat skinned fibres, by extraction of endogenous TnC and consecutive reconstitution with either slow or fast recombinant TnC. A mutant (VG2), lacking the regulatory site II, was also used to distinguish the role of each regulatory site. 3. Fast tibialis fibres reconstituted with cardiac TnC exhibited a typical slow bepridil reactivity, while slow soleus fibres reincorporated with fast TnC displayed a typically fast reactivity to bepridil. These results indicated that the differential effect of bepridil in slow and fast fibres is related to the TnC isoform predominantly expressed in a fibre. 4. Experiments with the VG2 mutant demonstrated that BPD can achieve an increase in the Ca 2+ affinity in the absence of a functional site II. Thus, site I was necessary for the BPD effect to be independent of the Ca 2+ concentration. Moreover, the amplitude of the reinforcement in the Ca 2+ affinity, induced by the binding of bepridil to the TnC molecule, is dependent on the number of functional regulatory sites, the larger affinity reinforcement being detected when only one regulatory site (either site I or II) is functional.
KW - Bepridil
KW - Ca -sensitizer drug
KW - Skinned fibres
KW - TnC mutant
KW - TnC substitution
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U2 - 10.1038/sj.bjp.0703727
DO - 10.1038/sj.bjp.0703727
M3 - Article
C2 - 11090126
AN - SCOPUS:0033638152
VL - 131
SP - 1496
EP - 1502
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 7
ER -