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Biophys J, December 1999, p. 3010-3022, Vol. 77, No. 6
*Muscle Research Group, John Curtin School of Medical Research, Canberra, ACT 2601, Australia, and #Second Institute of Physiology, University of Heidelberg, Heidelberg D69120, Germany
Time-dependent effects of cysteine modification were
compared in skeletal ryanodine receptors (RyRs) from normal pigs and RyRMH (Arg615 to Cys615) from pigs
susceptible to malignant hyperthermia, using the oxidizing reagents
4,4'-dithiodipyridine (4,4'-DTDP) and 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB) or the reducing agent dithiothreitol (DTT). Normal and
RyRMH channels responded similarly to all reagents. DTNB (1 mM), either cytoplasmic (cis) or luminal
(trans), or 1 mM 4,4'-DTDP (cis)
activated RyRs, introducing an additional long open time constant.
4,4'-DTDP (cis), but not DTNB, inhibited channels after >5 min. Activation and inhibition were relieved by DTT (1-10 mM). DTT
(10 mM, cytoplasmic or luminal), without oxidants, activated RyRs, and
activation reversed with 1 mM DTNB. Control RyR activity was maintained
with 1 mM DTNB and 10 mM DTT present on the same or opposite sides of
the bilayer. We suggest that 1) 4,4'-DTDP and DTNB covalently modify
RyRs by oxidizing activating or inhibiting thiol groups; 2) a modified
thiol depresses mammalian skeletal RyR activity under control
conditions; 3) both the activating thiols and the modified thiols,
accessible from either cytoplasm or lumen, reside in the transmembrane
region; 4) some cardiac sulfhydryls are unavailable in skeletal RyRs;
and 5) Cys615 in RyRMH is functionally
unimportant in redox cycling.
Biophys J, December 1999, p. 3010-3022, Vol. 77, No. 6
© 1999 by the Biophysical Society 0006-3495/99/12/3010/13 $2.00
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