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Biophys J, April 2001, p. 1769-1782, Vol. 80, No. 4

Arg615Cys Substitution in Pig Skeletal Ryanodine Receptors Increases Activation of Single Channels by a Segment of the Skeletal DHPR II-III Loop

Esther M. Gallant, Suzanne Curtis, Suzy M. Pace, and Angela F. Dulhunty

Muscle Research Group, John Curtin School of Medical Research, P.O. Box 334, Canberra, ACT 2601, Australia

The effect of peptides, corresponding to sequences in the skeletal muscle dihydropyridine receptor II-III loop, on Ca2+ release from sarcoplasmic reticulum (SR) and on ryanodine receptor (RyR) calcium release channels have been compared in preparations from normal and malignant hyperthermia (MH)-susceptible pigs. Peptide A (Thr671-Leu690; 36 µM) enhanced the rate of Ca2+ release from normal SR (SRN) and from SR of MH-susceptible muscle (SRMH) by 10 ± 3.2 nmole/mg/min and 76 ± 9.7 nmole/mg/min, respectively. Ca 2+ release from SRN or SRMH was not increased by control peptide NB (Gly689-Lys708). AS (scrambled A sequence; 36 µM) did not alter Ca 2+ release from SRN, but increased release from SRMH by 29 ± 4.9 nmoles/mg/min. RyR channels from MH-susceptible muscle (RyRMH) were up to about fourfold more strongly activated by peptide A (>= 1 nM) than normal RyR channels (RyRN) at -40 mV. Neither NB or AS activated RyRN. RyRMH showed an ~1.8-fold increase in mean current with 30 µM AS. Inhibition at +40 mV was stronger in RyRMH and seen with peptide A (>= 0.6 µM) and AS (>= 0.6 µM), but not NB. These results show that the Arg615Cys substitution in RyRMH has multiple effects on RyRs. We speculate that enhanced DHPR activation of RyRs may contribute to increased Ca2+ release from SR in MH-susceptible muscle.

Biophys J, April 2001, p. 1769-1782, Vol. 80, No. 4
© 2001 by the Biophysical Society   0006-3495/01/04/1769/14  $2.00


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