The C terminus (amino acids 75-94) and the linker region (amino acids 42-54) of the Ca2+-binding protein S100A1 differentially enhance sarcoplasmic Ca2+ release in murine skinned skeletal muscle fibers.
S100A1, a Ca2+-binding protein of the EF-hand type, is most highly expressed in striated muscle and has previously been shown to interact with the skeletal muscle sarcoplasmic reticulum (SR) Ca2+ release channel/ryanodine receptor (RyR1) isoform. However, it was unclear whether S100A1/RyR1 interaction could modulate SR Ca2+ handling and contractile properties in skeletal muscle fibers. Since S100A1 protein is differentially expressed in fast- and slow-twitch skeletal muscle, we used saponin-skinned murine Musculus extensor digitorum longus (EDL) and Musculus soleus (Soleus) fibers to assess the impact of S100A1 protein on SR Ca2+ release and isometric twitch force in functionally intact permeabilized muscle fibers. S100A1 equally enhanced caffeine-induced SR Ca2+ release and Ca2+-induced isometric force transients in both muscle preparations in a dose-dependent manner. Introducing a synthetic S100A1 peptide model (devoid of EF-hand Ca2+-binding sites) allowed identification of the S100A1 C terminus (amino acids 75-94) and hinge region (amino acids 42-54) to differentially enhance SR Ca2+ release with a nearly 3-fold higher activity of the C terminus. These effects were exclusively based on enhanced SR Ca2+ release as S100A1 influenced neither SR Ca2+ uptake nor myofilament Ca2+ sensitivity/cooperativity in our experimental setting. In conclusion, our study shows for the first time that S100A1 augments contractile performance both of fast- and slow-twitch skeletal muscle fibers based on enhanced SR Ca2+ efflux at least mediated by the C terminus of S100A1 protein. Thus, our data suggest that S100A1 may serve as an endogenous enhancer of SR Ca2+ release and might therefore be of physiological relevance in the process of excitation-contraction coupling in skeletal muscle.
Abteilung Innere Medizin III (Kardiologie), Universität Heidelberg, 69115 Heidelberg, Germany.
Patrick
P
Most
Andrew
A
Remppis
Cornelia
C
Weber
Juliane
J
Bernotat
Philipp
P
Ehlermann
Sven T
ST
Pleger
Wolfgang
W
Kirsch
Martin
M
Weber
Dietmar
D
Uttenweiler
Godfrey L
GL
Smith
Hugo A
HA
Katus
Rainer H A
RH
Fink
D000595:Amino Acid Sequence; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects / Q000378:metabolism; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D009418:S100 Proteins; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism
D002135:Calcium-Binding Proteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D009418:S100 Proteins; C110294:S100A1 protein; D002110:Caffeine