Activation of the Cardiac Ryanodine Receptor by Sulfhydryl Oxidation is Modified by Mg2+ and ATP |
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Authors: | KR Eager AF Dulhunty |
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Institution: | (1) Muscle Research Group, John Curtin School of Medical Research, PO Box 334, Canberra, ACT 2601, Australia, AU |
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Abstract: | The reactive disulfide 4,4′-dithiodipyridine (4,4′DTDP) was added to single cardiac ryanodine receptors (RyRs) in lipid bilayers.
The activity of native RyRs, with cytoplasmic (cis) Ca2+] of 10−7
m (in the absence of Mg2+ and ATP), increased within ∼1 min of addition of 1 mm 4,4′-DTDP, and then irreversibly ceased 5 to 6 min after the addition. Channels, inhibited by either 1 mm
cis Mg2+ (10−7
m
cis Ca2+) or by 10 mm
cis Mg2+ (10−3
m
cis Ca2+), or activated by 4 mm ATP (10−7
m
cis Ca2+), also responded to 1 mm
cis 4,4′-DTDP with activation and then loss of activity. P
o
and mean open time (T
o
) of the maximally activated channels were lower in the presence of Mg2+ than in its absence, and the number of openings within the long time constant components of the open time distribution was
reduced. In contrast to the reduced activation by 1 mm 4,4′-DTDP in channels inhibited by Mg2+, and the previously reported enhanced activation by 4,4′-DTDP in channels activated by Ca2+ or caffeine (Eager et al., 1997), the activation produced by 1 mm
cis 4,4′-DTDP was the same in the presence and absence of ATP. These results suggest that there is a physical interaction between
the ATP binding domain of the cardiac RyR and the SH groups whose oxidation leads to channel activation.
Received: 8 September 1997/Revised: 20 January 1998 |
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Keywords: | : Reactive disulfides — Sarcoplasmic reticulum — Sulfhydryl oxidation — Calcium-induced activation — Calcium-induced inhibition |
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