The sarcoplasmic reticulum of skeletal muscle plays a key role in the regulation of intracellular Ca 2ϩ concentration. Ca 2ϩ ions are released from this intracellular Ca 2ϩ storage by means of the ryanodine receptor and resequestered by the Ca 2ϩ -ATPase pump [1] [2] [3] . The activity of the ryanodine receptor is controlled primarily by Ca 2ϩ and modulated by several endogenous ligands (including Mg 2ϩ and ATP). Most of these compounds act on the cytosolic side of the channel [4] [5] [6] .

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... odine receptor-Ca 2ϩ channel activity is also regulated by luminal Ca 2ϩ [7, 8] . To date, annexin VI [9] and Ca 2ϩ are the only molecules proposed to act at the luminal side of the Ca 2ϩ channel. Pharmacological substances such as caffeine and ryanodine may activate and/or inhibit the ryanodine receptor in intact and skinned striated muscle fibers and isolated structures containing the ryanodine receptor [6, 10-12]. The effects of caffeine are influenced by cytosolic and luminal Ca 2ϩ [10, 13] . Several studies have shown that 4-chloro-m-cresol (4-CmC), a new pharmacological substance, is a potent activator of the ryanodine receptor on muscular and nonmuscular structures [14] [15] [16] [17] [18] . 4-CmC has been reported to stimulate Ca 2ϩ -activated 3H ryanodine binding on heavy sarcoplasmic reticulum vesicles from rabbit back muscles and to induce transient caffeine-like contractures in intact and malignant hyperthermia-susceptible skeletal muscle fibers at concentrations tenfold lower than for caffeine [15, 16] . These authors proposed that the difference in the sensitivity of skeletal muscles to caffeine and 4-CmC could be related to different binding sites on the ryanodine receptor [16] . The binding site for caffeine is on the cytosolic side of the ryanodine receptor [19] . suggested that a stronger activation of the isolated ryanodine receptor channel by 4-CmC (when applied to the luminal side of the ryanodine receptor) may be explained by the presence of a 4-CmC S. CHOISY et al. Fig. 6 . Caffeine concentration-response curves for edl saponin-skinned fibers obtained under different sarcoplasmic reticulum Ca 2؉ loading conditions. The amplitudes of caffeine contractures are expressed as a percentage of maximal caffeine responses. Curves were fitted by using the Hill equation, and a logarithm scale is used in abscissa. Experiments were performed at 22°C.