Inhibition and Rapid Recovery of Ca 2+ Current During Ca 2+ Release From Sarcoplasmic Reticulum in Guinea Pig Ventricular Myocytes

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Abstract
We have investigated the modulation of the L-type Ca 2+ channel by Ca 2+ released from the sarcoplasmic reticulum (SR) in single guinea pig ventricular myocytes under whole-cell voltage clamp. [Ca 2+ ] i was monitored by fura 2. By use of impermeant monovalent cations in intracellular and extracellular solutions, the current through Na + channels, K + channels, nonspecific cation channels, and the Na + -Ca 2+ exchanger was effectively blocked. By altering the amount of Ca 2+ loading of the SR, the time course of the Ca 2+ current (I Ca ) could be studied during various amplitudes of Ca 2+ release. In the presence of a large Ca 2+ release, fast inhibition of I Ca occurred, whereas on relaxation of [Ca 2+ ] i , fast recovery was observed. The time course of this transient inhibition of I Ca reflected the time course of [Ca 2+ ] i . However, the inhibition seen in the first 50 ms, ie, the time of net Ca 2+ release from the SR, exceeded the inhibition observed later during the pulse, suggesting the existence of a higher [Ca 2+ ] near the channel during this time. Transient inhibition of I Ca during Ca 2+ release was observed to a similar degree at all potentials. It could still be observed in the presence of intracellular ATP-γ-S and of cAMP. Therefore, we conclude that the modulation of I Ca by Ca 2+ release from the SR is not related to dephosphorylation. It could be related to a reduction in the driving force and to a direct inhibition of the channel by [Ca 2+ ] i . The observation that the degree of inhibition does not depend on membrane potential suggests that the Ca 2+ binding site for this modulation is located outside the pore. The transient nature of the modulation of I Ca by Ca 2+ release will contribute to the recovery of I Ca during prolonged action potentials.