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

Abstract

Large-conductance, voltage- and calcium-activated potassium (BK, or KCa1.1) channels are ubiquitously expressed in electrically excitable and non-excitable cells1,2, either as α-subunit (BKα) tetramers or together with tissue specific auxiliary β-subunits (β1–β4)3,4,5. 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 (−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.

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Figure 1: Identification of LRRC26 as a BK channel accessory protein in LNCaP cells.
Figure 2: Co-expression of LRRC26 with BKα is necessary and sufficient for formation of the LNCaP-type low- V 1/2 BK channels.
Figure 3: Properties of LRRC26 protein.
Figure 4: The LRRC26 modulatory mechanism in the context of the BK channel voltage-dependent allosteric gating model.

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Acknowledgements

We are grateful to I. Pastan and X. F. Liu for the generous gift of LRRC26 antibody and plasmids. We thank J. Trimmer for discussion and W. Li, L. Scott, J. Greeson, X. Chen and H. Liu for reading the manuscript. We thank A. Hall, H. Cha and U. Bagaria for research assistance. Mass spectrometry was performed at the UC Davis Proteomics Facility. J.Y. acknowledges postdoctoral fellowship support from the American Heart Association.

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J.Y. performed the experiments. J.Y. and R.W.A. designed the research, analysed the data and wrote the paper.

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Correspondence to Richard W. Aldrich.

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The authors declare no competing financial interests.

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Yan, J., Aldrich, R. LRRC26 auxiliary protein allows BK channel activation at resting voltage without calcium. Nature 466, 513–516 (2010). https://doi.org/10.1038/nature09162

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