Abstract
The effect of peptides, corresponding to sequences in the skeletal muscle dihydropyridine receptor II-III loop, on Ca 2+ 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 (Thr 671-Leu 690; 36 μM) enhanced the rate of Ca 2+ release from normal SR (SR N) and from SR of MH-susceptible muscle (SR MH) by 10 ± 3.2 nmole/mg/min and 76 ± 9.7 nmole/mg/min, respectively. Ca 2+ release from SR N or SR MH was not increased by control peptide NB (Gly 689-Lys 708). AS (scrambled A sequence; 36 μM) did not alter Ca 2+ release from SR N, but increased release from SR MH by 29 ± 4.9 nmoles/mg/min. RyR channels from MH-susceptible muscle (RyR MH) were up to about fourfold more strongly activated by peptide A (≥1 nM) than normal RyR channels (RyR N) at −40 mV. Neither NB or AS activated RyR N. RyR MH showed an ∼1.8-fold increase in mean current with 30 μM AS. Inhibition at +40 mV was stronger in RyR MH and seen with peptide A (≥0.6 μM) and AS (≥0.6 μM), but not NB. These results show that the Arg 615Cys substitution in RyR MH has multiple effects on RyRs. We speculate that enhanced DHPR activation of RyRs may contribute to increased Ca 2+ release from SR in MH-susceptible muscle.
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