Rat chromaffin cells express an interesting diversity of Ca(2+)-dependent K+ channels, including a voltage-independent, small-conductance, apamin-sensitive SK channel and two variants of voltage-dependent, large-conductance BK channels. The two BK channel variants are differentially segregated among chromaffin cells, such that BK current is completely inactivating in about 75-80% of rat chromaffin cells, while the remainder express a mix of inactivating and non-inactivating current or mostly non-inactivating BKs current. The single-channel conductance of BKi channels is identical to that of BKs channels. Although rates of current activation are similar in the two variants, the deactivation kinetics of the two channels also differ. Furthermore, BKi channels are somewhat less sensitive to scorpion toxins than BKs channels. The slow component of BKi channel deactivation may be an important determinant of the functional role of these channels. During blockade of SK current, cells with BKi current fire tonically during sustained depolarizing current injection, whereas cells with BKs current tend to fire only a few action potentials before becoming quiescent. The ability to repetitively fire requires functional BKi channels, since partial blockade of BKi channels by CTX makes a BKi cell behave much like a BKs cell. In contrast, the physiological significance of BKi inactivation may arise from the ability of secretagogue-induced [Ca2+]i elevations to regulate the availability of BKi channels during subsequent action potentials (Herrington et al., 1995). By reducing the number of BK channels available for repolarization, the time course of action potentials may be prolonged. This possibility remains to be tested directly. These results raise a number of interesting questions pertinent to the control of secretion in rat adrenal chromaffin cells. An interesting hypothesis is that cells with a particular kind of BK current may reflect particular subpopulations of chromaffin cells. These subpopulations might differ either in the nature of the material secreted from the cell (e.g., Douglass and Poisner, 1965) or in the responsiveness to particular secretagogues. The differences in electrical behavior between cells with BKi and BKs current suggest that the pattern of secretion that might be elicited by a single type of stimulus could differ. For BKi cells, secretion may occur in a tonic fashion during sustained depolarization, while secretion from cells with BKs current may be more phasic. In the absence of specific structural information about the domains responsible for inactivation of BKi channels, our understanding of the mechanism of inactivation remains indirect. BKi inactivation shares many features with N-terminal inactivation of voltage-dependent K+ channels. However, there are provocative differences between the two types of inactivation which require us to propose that the native inactivation domain of BKi channels may occlude access of permeant ions to the BK channel permeation pathway in a position at some distance from the actual mouth of the channel. Further understanding of the structural and mechanistic basis of inactivation of BKi channels promises to provide new insights into both the cytoplasmic topology of BK channels and the Ca(2+)- and voltage-dependent steps involved in channel activation.