Modification of excitation‐contraction coupling by 4‐chloro‐m‐cresol in voltage‐clamped cut muscle fibres of the frog (R. pipiens)

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Abstract
1 The effect of 5 μm 4-chloro-m-cresol (4-CmC) on voltage-controlled Ca2+ release was studied in cut muscle fibres of the frog loaded with internal solutions containing 15 mM EGTA. Fibres were voltage clamped using a double Vaseline gap system, and Ca2+ signals were recorded with the fluorescent indicator dye fura-2 2 Resting intracellular free Ca2+ concentration increased from 61 to 100 nm upon application of 4-CmC. 3 Both peak rate of release of intracellularly stored Ca2+ and the steady level attained after 50 ms of depolarization increased, but the potentiation of the latter was more pronounced (by a factor of 1.7 versus 1.3). The voltage of half-maximal activation remained unchanged. 4 Non-linear intramembranous charge movements showed no significant change in voltage dependence while the maximal charge displaced by depolarization increased by 25%. 5 The dependence of peak release flux on total intramembranous charge was not different in 4-CmC, but for the steady level of release the steepness of the relation increased by a factor of 1.3. 6 The stimulating effect of 5 μm 4-CmC on depolarization-induced Ca2+ release resembled the potentiation by 0.5 mm caffeine. However, 0.5 mm caffeine increased the peak and steady levels of the release rate by a similar factor and caused no increase in the resting free calcium concentration, indicating different modes of action of the two substances. 7 Neither 5 μm 4-CmC nor 0.5 mm caffeine led to a loss of voltage control of Ca2+ release during repolarization after short depolarizations, as has been reported previously for caffeine. Potentiated Ca2+ release could be terminated by repolarization as fast as under control conditions both with 15 mm and 0.1 mm internal EGTA. 8 The effects of 4-CmC may result from a direct opening of the release channel combined with an enhancement of the transduction mechanism that couples channel opening to displacement of voltage sensor charges.

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