CaV1.3-driven SK channel activation regulates pacemaking and spike frequency adaptation in mouse chromaffin cells

Mouse chromaffin cells (MCCs) fire spontaneous action potentials (APs) at rest. Cav1.3 L-type calcium channels sustain the pacemaker current, and their loss results in depolarized resting potentials (Vrest ), spike broadening, and remarkable switches into depolarization block after BayK 8644 application. A functional coupling between Cav1.3 and BK channels has been reported but cannot fully account for the aforementioned observations. Here, using Cav1.3/ mice, we investigated the role of Cav1.3 on SK channel activation and how this functional coupling affects the firing patterns induced by sustained current injections. MCCs express SK1–3 channels whose tonic currents are responsible for the slow irregular firing observed at rest. Percentage of frequency increase induced by apamin was found inversely correlated to basal firing frequency. Upon stimulation, MCCs build-up Cav1.3-dependent SK currents during the interspike intervals that lead to a notable degree of spike frequency adaptation (SFA). The major contribution of Cav1.3 to the subthreshold Ca2charge during an AP-train rather than a specific molecular coupling to SK channels accounts for the reduced SFA of Cav1.3/ MCCs. Low adaptation ratios due to reduced SK activation associated with Cav1.3 deficiency prevent the efficient recovery of NaV channels from inactivation. This promotes a rapid decline of AP amplitudes and facilitates early onset of depolarization block following prolonged stimulation. Thus, besides serving as pacemaker, Cav1.3 slows down MCC firing by activating SK channels that maintain NaV channel availability high enough to preserve stable AP waveforms, even upon high-frequency stimulation of chromaffin cells during stress responses.