Proximal clustering between BK and Ca V 1.3 channels promotes functional coupling and BK channel activation at low voltage.

Ca _V -channel dependent activation of BK channels is critical for feedback control of both calcium influx and cell excitability. Here we addressed the functional and spatial interaction between BK and Ca _V 1.3 channels, unique Ca _V 1 channels that activate at low voltages. We found that when BK and Ca _V 1.3 channels were co-expressed in the same cell, BK channels started activating near -50 mV, ~30 mV more negative than for activation of co-expressed BK and high-voltage activated Ca _V 2.2 channels. In addition, single-molecule localization microscopy revealed striking clusters of Ca _V 1.3 channels surrounding clusters of BK channels and forming a multi-channel complex both in a heterologous system and in rat hippocampal and sympathetic neurons. We propose that this spatial arrangement allows tight tracking between local BK channel activation and the gating of Ca _V 1.3 channels at quite negative membrane potentials, facilitating the regulation of neuronal excitability at voltages close to the threshold to fire action potentials.