BK Ca -Cav Channel Complexes Mediate Rapid and Localized Ca 2+ -Activated K + Signaling

Abstract

Large-conductance calcium- and voltage-activated potassium channels (BK Ca ) are dually activated by membrane depolarization and elevation of cytosolic calcium ions (Ca 2+ ). Under normal cellular conditions, BK Ca channel activation requires Ca 2+ concentrations that typically occur in close proximity to Ca 2+ sources. We show that BK Ca channels affinity-purified from rat brain are assembled into macromolecular complexes with the voltage-gated calcium channels Cav1.2 (L-type), Cav2.1 (P/Q-type), and Cav2.2 (N-type). Heterologously expressed BK Ca -Cav complexes reconstitute a functional “Ca 2+ nanodomain” where Ca 2+ influx through the Cav channel activates BK Ca in the physiological voltage range with submillisecond kinetics. Complex formation with distinct Cav channels enables BK Ca -mediated membrane hyperpolarization that controls neuronal firing pattern and release of hormones and transmitters in the central nervous system.