title: Ca(V)1.3-driven SK channel activation regulates pacemaking and spike frequency adaptation in mouse chromaffin cells.
abstract: Mouse chromaffin cells (MCCs) fire spontaneous action potentials (APs) at rest. Ca(v)1.3 L-type calcium channels sustain the pacemaker current, and their loss results in depolarized resting potentials (V(rest)), spike broadening, and remarkable switches into depolarization block after BayK 8644 application. A functional coupling between Ca(v)1.3 and BK channels has been reported but cannot fully account for the aforementioned observations. Here, using Ca(v)1.3(-/-) mice, we investigated the role of Ca(v)1.3 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 Ca(v)1.3-dependent SK currents during the interspike intervals that lead to a notable degree of spike frequency adaptation (SFA). The major contribution of Ca(v)1.3 to the subthreshold Ca(2+) charge during an AP-train rather than a specific molecular coupling to SK channels accounts for the reduced SFA of Ca(v)1.3(-/-) MCCs. Low adaptation ratios due to reduced SK activation associated with Ca(v)1.3 deficiency prevent the efficient recovery of Na(V) 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, Ca(v)1.3 slows down MCC firing by activating SK channels that maintain Na(V) channel availability high enough to preserve stable AP waveforms, even upon high-frequency stimulation of chromaffin cells during stress responses.
authors.affiliation: Department of Drug Science, Laboratory of Cellular and Molecular Neuroscience, Nanostructured Interfaces and Surfaces Center, 10125 Torino, Italy.
authors.forename: David H F
authors.initials: DH
authors.lastname: Vandael
authors.forename: Annalisa
authors.initials: A
authors.lastname: Zuccotti
authors.forename: Joerg
authors.initials: J
authors.lastname: Striessnig
authors.forename: Emilio
authors.initials: E
authors.lastname: Carbone
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology*; D019439:Chromaffin Cells / Q000187:drug effects / Q000502:physiology*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D055724:Electrophysiological Phenomena; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D060888:Real-Time Polymerase Chain Reaction; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects / Q000502:physiology*; D015222:Sodium Channels / Q000187:drug effects
chemical_list: C485995:Cacna1d protein, mouse; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D018076:DNA, Complementary; D051640:Small-Conductance Calcium-Activated Potassium Channels; D015222:Sodium Channels; D001030:Apamin; D012313:RNA; D002118:Calcium