BKca-channels: After all it's Ca2+ only

Berkefeld H, Fakler B

Large conductance Ca(2+)- and voltage-activated potassium channels (BKCa) shape neuronal excitability and signal transduction. This reflects the integrated influences of transmembrane voltage and intracellular calcium concentration ([Ca(2+)]i) that gate the channels. This dual gating has been mainly studied as voltage-triggered gating modulated by defined steady-state [Ca(2+)]i, a paradigm that does not approximate native conditions. Here we use submillisecond changes of [Ca(2+)]i to investigate the time course of the Ca(2+)-triggered gating of BKCa channels expressed in Chinese hamster ovary cells at distinct membrane potentials in the physiological range. The results show that Ca(2+) can effectively gate BKCa channels and that Ca(2+) gating is largely different from voltage-driven gating. Most prominently, Ca(2+) gating displays a pronounced delay in the millisecond range between Ca(2+) application and channel opening (pre-onset delay) and exhibits slower kinetics across the entire [Ca(2+)]i-voltage plane. Both characteristics are selectively altered by co-assembled BKβ4 or an epilepsy-causing mutation that either slows deactivation or speeds activation and reduces the pre-onset delay, respectively. Similarly, co-assembly of the BKCa channels with voltage-activated Ca(2+) (Cav) channels, mirroring the native configuration, decreased the pre-onset delay to submillisecond values. In BKCa-Cav complexes, the time course of the hyperpolarizing K(+)-current response is dictated by the Ca(2+) gating of the BKCa channels. Consistent with Cav-mediated Ca(2+) influx, gating was fastest at hyperpolarized potentials, but decreased with depolarization of the membrane potential. Our results demonstrate that under experimental paradigms meant to approximate the physiological conditions BKCa channels primarily operate as ligand-activated channels gated by intracellular Ca(2+) and that Ca(2+) gating is tuned for fast responses in neuronal BKCa-Cav complexes.

View fulltext online at J Neurosci.