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 (Ca²⁺). Under normal cellular conditions, BK_Ca channel activation requires Ca²⁺ concentrations that typically occur in close proximity to Ca²⁺ 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 “Ca²⁺ nanodomain” where Ca²⁺ 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.