Differential Regulation of Action Potentials by Inactivating and Noninactivating BK Channels in Rat Adrenal Chromaffin Cells

Abstract

Large-conductance Ca(2+)-activated K(+) (BK) channels can regulate cellular excitability in complex ways because they are able to respond independently to two distinct cellular signals, cytosolic Ca(2+) and membrane potential. In rat chromaffin cells (RCC), inactivating BK(i) and noninactivating (BK(s)) channels differentially contribute to RCC action potential (AP) firing behavior. However, the basis for these differential effects has not been fully established. Here, we have simulated RCC action potential behavior, using Markovian models of BK(i) and BK(s) current and other RCC currents. The analysis shows that BK current influences both fast hyperpolarization and afterhyperpolarization of single APs and that, consistent with experimental observations, BK(i) current facilitates repetitive firing of APs, whereas BK(s) current does not. However, the key functional difference between BK(i) and BK(s) current that accounts for the differential firing is not inactivation but the more negatively shifted activation range for BK(i) current at a given [Ca(2+)].

CaV1.3-Driven SK Channel Activation Regulates Pacemaking and Spike Frequency Adaptation in Mouse Chromaffin Cells

“…This could explain why Ca v 1.3 Ϫ/Ϫ MCCs typically responded with a train of high-frequency spikes followed by sustained depolarizations after LTCCs (Ca v 1.2) were boosted with BayK 8644 Vandael et al, 2010). These results agree with recent observations on RCCs that respond with similar depolarization blocks upon increased current injections when SK channels were blocked and fast inactivating BK channels were absent (as is the case for Ca v 1.3 Ϫ/Ϫ MCCs) (Sun et al, 2009). …”

Loss of Cav1.3 Channels Reveals the Critical Role of L-Type and BK Channel Coupling in Pacemaking Mouse Adrenal Chromaffin Cells

“…We found of great significance that, whereas WTMCCs possess mainly BK i channels and smaller fractions of BK s , KO-MCCs possessed mostly BK s channels, indicating preferential coupling between BK i and Cav1.3 channels. Because BK i channel inactivation is associated with the presence of a specific BK ␤ 2 subunit that shifts channel activation toward more negative voltages at a given Ca 2ϩ and inactivate open channels (Xia et al, 2000;Sun et al, 2009), our data suggest also that loss of Cav1.3 channels may lead to the loss of BK ␤ 2 subunits. This could also indicate that ␤ 2 is the critical element regulating the close coupling between Cav1.3 and BK i channels.…”

“…8b, black trace). It is important to notice that, because fast inactivating BK i channels activate at more negative potentials with respect to non-inactivating BK s channels (Sun et al, 2009), it is likely that BK i channels carry most of the slow prespike outward current. BK s channels are expected to sustain the postspike current together with BK i channels.…”

“…This L-type current is not only responsible for the prespike inward current driving WT-MCC activity but originates the slow BK current that activates during the prespike period and most of the fast BK component during spikes. The former current is likely to be mostly carried by BK i channels that open at relatively low voltages at a given Ca 2ϩ (Sun et al, 2009), whereas the latter is sustained by both BK i and BK s channels. Both currents are strongly attenuated in KO-MCCs.…”

Contribution of BK channels to action potential repolarisation at minimal cytosolic Ca2+ concentration in chromaffin cells

“…Thus, cells expressing mostly BK i are capable to produce more sustained AP firing than those expressing mainly BK s channels [24,42]. This differential behaviour has been attributed to the more negatively shifted activation range for BK i channels relative to that of BK s channels [44].…”