INHIBITION AND RAPID RECOVERY OF CA2+ CURRENT DURING CA2+ RELEASE FROM SARCOPLASMIC-RETICULUM IN GUINEA-PIG VENTRICULAR MYOCYTES

We have investigated the modulation of the L-type Ca2+ channel by Ca2+ released from the sarcoplasmic reticulum (SR) in single guinea pig ventricular myocytes under whole-cell voltage clamp. [Ca2+](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+-Ca2+ exchanger was effectively blocked. By altering the amount of Ca2+ loading of the SR, the time course of the Ca2+ current (I-Ca) could be studied during various amplitudes of Ca2+ release. In the presence of a large Ca2+ release, fast inhibition of I-Ca occurred, whereas on relaxation of [Ca2+](i), fast recovery was observed. The time course of this transient inhibition of I-Ca reflected the time course of [Ca2+](i). However, the inhibition seen in the first 50 ms, ie, the time of net Ca2+ release from the SR, exceeded the inhibition observed later during the pulse, suggesting the existence of a higher [Ca2+] near the channel during this time. Transient inhibition of I-Ca during Ca2+ release was observed to a similar degree at all potentials. It could still be observed in the presence of intracellular ATP-gamma-S and of cAMP. Therefore, we conclude that the modulation of I-Ca by Ca2+ 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 [Ca2+](i). The observation that the degree of inhibition does not depend on membrane potential suggests that the Ca2+ binding site for this modulation is located outside the pore. The transient nature of the modulation of I-Ca by Ca2+ release will contribute to the recovery of I-Ca during prolonged action potentials.