LRRC26 auxiliary protein allows BK channel activation at resting voltage without calcium

Large-conductance, voltage-and calcium-activated potassium (BK, or K(Ca)1.1) channels are ubiquitously expressed in electrically excitable and non-excitable cells(1,2), either as alpha-subunit (BK alpha) tetramers or together with tissue specific auxiliary beta-subunits (beta 1-beta 4)(3-5). Activation of BK channels typically requires coincident membrane depolarization and elevation in free cytosolic Ca2+ concentration ([Ca2+](i))(6,7), which are not physiological conditions for most non-excitable cells. Here we present evidence that in non-excitable LNCaP prostate cancer cells, BK channels can be activated at negative voltages without rises in [Ca2+](i) through their complex with an auxiliary protein, leucine-rich repeat (LRR)-containing protein 26 (LRRC26). LRRC26 modulates the gating of a BK channel by enhancing the allosteric coupling between voltage-sensor activation and the channel's closed-open transition. This finding reveals a novel auxiliary protein of a voltage- gated ion channel that gives an unprecedentedly large negative shift (similar to-140 mV) in voltage dependence and provides a molecular basis for activation of BK channels at physiological voltages and calcium levels in non-excitable cells.