THE SUPPRESSION OF CA2-DEPENDENT AND VOLTAGE-DEPENDENT K+ CURRENT DURING MACHR ACTIVATION IN RAT ADRENAL CHROMAFFIN CELLS()

1. The mechanism by which muscarine, ionomycin or caffeine results in suppression of Ca2+- and voltage-dependent outward current in rat adre nal chromaffin cells was evaluated using both whole-cell voltage clamp and single channel recording. 2. The whole-cell current activated fol lowing the elevation of the cytosolic calcium concentration ([Ca2+](i) ) by muscarine inactivates with a time course comparable to that of si ngle Ca2+- and voltage-dependent potassium (BK) channels. 3. The whole -cell inactivating current is pharmacologically similar to BK current. 4. The voltage dependence of inactivation and rate of recovery from i nactivation are qualitatively similar for both whole-cell current and ensemble averages of single BK channels. Furthermore, changes in the r ate of whole-cell current inactivation track expected changes in subme mbrane [Ca2+]. 5. The suppression of outward current can be accounted for solely by inactivation of BK channels and does not depend on the m eans by which [Ca2+](i) is elevated. 6. Muscarinic acetylcholine recep tor (mAChR) activation, changes in holding potential (-50 to -20 mV), and step depolarizations of different amplitude and duration were test ed for their ability to elevate [Ca2+](i) and thereby regulate the ava ilability of BK current for activation. 7. Following muscarine-induced elevation of [Ca2+](i) at holding potentials positive to -40 mV, the availability of BK current for activation was typically reduced by mor e than 50 %. 8. Holding potentials in the range of -50 to -20 mV produ ced only slight alterations in the availability of BK current for acti vation. 9. Step depolarizations that cause maximal rates of Ca2+ influ x (0 to +10 mV) must exceed 200 ms to reduce the availability of BK cu rrent by approximately 50 %. 10. The results show that the muscarine-i nduced elevation of [Ca2+](i) produces a profound reduction in the ava ilability of BK channels for activation at membrane potentials likely to be physiologically meaningful. Although depolarization-induced Ca2 influx can inactivate BK current, we propose that short duration depo larizations that occur during normal electrical activity will not sign ificantly alter BK channel availability.