The LRRC family of BK channel regulatory subunits: potential roles in health and disease

Gonzalez-Perez V, Zhou Y, Ciorba Matthew A, Lingle CJ

J Physiol. 2022 Jan 10. doi: 10.1113/JP281952.

Slow recovery from fast inactivation of Nav1.3 channels: a common gating mechanism shared in sweet- and sour-sensing cells.
Lingle CJ.
Pflugers Arch. 2021 Jun;473(6):855-857. doi: 10.1007/s00424-021-02575-6. Epub 2021 May 10.

Nav1.3 and FGF14 are primary determinants of the TTX-sensitive sodium current in mouse adrenal chromaffin cells.
Martinez-Espinosa PL, Yang C, Xia XM, Lingle CJ.
J Gen Physiol. 2021 Apr 5;153(4):e202012785. doi: 10.1085/jgp.202012785.

Fast inactivation of Nav current in rat adrenal chromaffin cells involves two independent inactivation pathways.
Martinez-Espinosa PL, Neely A, Ding J, Lingle CJ.
J Gen Physiol. 2021 Apr 5;153(4):e202012784. doi: 10.1085/jgp.202012784.

Goblet cell LRRC26 regulates BK channel activation and protects against colitis in mice.
Gonzalez-Perez V, Martinez-Espinosa PL, Sala-Rabanal M, Bharadwaj N, Xia XM, Chen AC, Alvarado D, Gustafsson JK, Hu H, Ciorba MA, Lingle CJ.
Proc Natl Acad Sci U S A. 2021 Jan 19;118(3):e2019149118. doi: 10.1073/pnas.2019149118.

The functionally relevant site for paxilline inhibition of BK channels.
Zhou Y, Xia XM, Lingle CJ.
Proc Natl Acad Sci U S A. 2020 Jan 14;117(2):1021-1026. doi: 10.1073/pnas.1912623117. Epub 2019 Dec 26.

LRRC52 regulates BK channel function and localization in mouse cochlear inner hair cells.
Lingle CJ, Martinez-Espinosa PL, Yang-Hood A, Boero LE, Payne S, Persic D, V-Ghaffari B, Xiao M, Zhou Y, Xia XM, Pyott SJ, Rutherford MA.
Proc Natl Acad Sci U S A. 2019 Sep 10;116(37):18397-18403. doi: 10.1073/pnas.1907065116. Epub 2019 Aug 26.

Regulation of BK Channels by Beta and Gamma Subunits.
Gonzalez-Perez V, Lingle CJ.
Annu Rev Physiol. 2019 Feb 10;81:113-137. doi: 10.1146/annurev-physiol-022516-034038.

Regulatory γ1 subunits defy symmetry in functional modulation of BK channels.
Gonzalez-Perez V, Ben Johny M, Xia XM, Lingle CJ.
Proc Natl Acad Sci U S A. 2018 Oct 2;115(40):9923-9928. doi: 10.1073/pnas.1804560115. Epub 2018 Sep 17.

BK channel inhibition by strong extracellular acidification.
Zhou Y, Xia XM, Lingle CJ.
Elife. 2018 Jul 2;7:e38060. doi: 10.7554/eLife.38060.

Threading the biophysics of mammalian Slo1 channels onto structures of an invertebrate Slo1 channel.
Zhou Y, Yang H, Cui J, Lingle CJ.
J Gen Physiol. 2017 Nov 6;149(11):985-1007. doi: 10.1085/jgp.201711845. Epub 2017 Oct 12.

Roles of Na+, Ca2+, and K+ channels in the generation of repetitive firing and rhythmic bursting in adrenal chromaffin cells.
Lingle CJ, Martinez-Espinosa PL, Guarina L, Carbone E.
Pflugers Arch. 2018 Jan;470(1):39-52. doi: 10.1007/s00424-017-2048-1. Epub 2017 Aug 3.

Knockout of the LRRC26 subunit reveals a primary role of LRRC26-containing BK channels in secretory epithelial cells.
Yang C, Gonzalez-Perez V, Mukaibo T, Melvin JE, Xia XM, Lingle CJ.
Proc Natl Acad Sci U S A. 2017 May 2;114(18):E3739-E3747. doi: 10.1073/pnas.1703081114. Epub 2017 Apr 17.

Engineering differential charge selectivity from a single structural template.
Zhou Y, Lingle CJ.
Proc Natl Acad Sci U S A. 2016 Nov 8;113(45):12610-12612. doi: 10.1073/pnas.1615847113. Epub 2016 Oct 28.

Knockout of Slo2.2 enhances itch, abolishes KNa current, and increases action potential firing frequency in DRG neurons.
Martinez-Espinosa PL, Wu J, Yang C, Gonzalez-Perez V, Zhou H, Liang H, Xia XM, Lingle CJ.
Elife. 2015 Nov 11;4:e10013. doi: 10.7554/eLife.10013.

Two classes of regulatory subunits coassemble in the same BK channel and independently regulate gating.
Gonzalez-Perez V, Xia XM, Lingle CJ.
Nat Commun. 2015 Sep 21;6:8341. doi: 10.1038/ncomms9341.

Cadmium-cysteine coordination in the BK inner pore region and its structural and functional implications.
Zhou Y, Xia XM, Lingle CJ.
Proc Natl Acad Sci U S A. 2015 Apr 21;112(16):5237-42. doi: 10.1073/pnas.1500953112. Epub 2015 Apr 6.

NAVigating a transition from single action potential firing to bursting in chromaffin cells.
Lingle CJ.
J Physiol. 2015 Feb 15;593(4):761-2. doi: 10.1113/jphysiol.2014.288464.

SLO3 auxiliary subunit LRRC52 controls gating of sperm KSPER currents and is critical for normal fertility.
Zeng XH, Yang C, Xia XM, Liu M, Lingle CJ.
Proc Natl Acad Sci U S A. 2015 Feb 24;112(8):2599-604. doi: 10.1073/pnas.1423869112. Epub 2015 Feb 9.

Paxilline inhibits BK channels by an almost exclusively closed-channel block mechanism.
Zhou Y, Lingle CJ.
J Gen Physiol. 2014 Nov;144(5):415-40. doi: 10.1085/jgp.201411259.

Knockout of the BK β2 subunit abolishes inactivation of BK currents in mouse adrenal chromaffin cells and results in slow-wave burst activity.
Martinez-Espinosa PL, Yang C, Gonzalez-Perez V, Xia XM, Lingle CJ.
J Gen Physiol. 2014 Oct;144(4):275-95. doi: 10.1085/jgp.201411253.

The Ca2+-activated K+ current of human sperm is mediated by Slo3.
Brenker C, Zhou Y, Müller A, Echeverry FA, Trötschel C, Poetsch A, Xia XM, Bönigk W, Lingle CJ, Kaupp UB, Strünker T.
Elife. 2014 Mar 26;3:e01438. doi: 10.7554/eLife.01438.

Functional regulation of BK potassium channels by γ1 auxiliary subunits.
Gonzalez-Perez V, Xia XM, Lingle CJ.
Proc Natl Acad Sci U S A. 2014 Apr 1;111(13):4868-73. doi: 10.1073/pnas.1322123111. Epub 2014 Mar 17.

Simultaneous knockout of Slo3 and CatSper1 abolishes all alkalization- and voltage-activated current in mouse spermatozoa.
Zeng XH, Navarro B, Xia XM, Clapham DE, Lingle CJ.
J Gen Physiol. 2013 Sep;142(3):305-13. doi: 10.1085/jgp.201311011.

Barium ions selectively activate BK channels via the Ca2+-bowl site.
Zhou Y, Zeng XH, Lingle CJ.
Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11413-8. doi: 10.1073/pnas.1204444109. Epub 2012 Jun 25.

Stereospecific binding of a disordered peptide segment mediates BK channel inactivation.
Gonzalez-Perez V, Zeng XH, Henzler-Wildman K, Lingle CJ.
Nature. 2012 May 3;485(7396):133-6. doi: 10.1038/nature10994.

LRRC52 (leucine-rich-repeat-containing protein 52), a testis-specific auxiliary subunit of the alkalization-activated Slo3 channel.
Yang C, Zeng XH, Zhou Y, Xia XM, Lingle CJ.
Proc Natl Acad Sci U S A. 2011 Nov 29;108(48):19419-24. doi: 10.1073/pnas.1111104108. Epub 2011 Nov 14.

Cysteine scanning and modification reveal major differences between BK channels and Kv channels in the inner pore region.
Zhou Y, Xia XM, Lingle CJ.
Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):12161-6. doi: 10.1073/pnas.1104150108. Epub 2011 Jul 5.

Deletion of the Slo3 gene abolishes alkalization-activated K+ current in mouse spermatozoa.
Zeng XH, Yang C, Kim ST, Lingle CJ, Xia XM.
Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5879-84. doi: 10.1073/pnas.1100240108. Epub 2011 Mar 22.

Inhibition of large-conductance Ca2+-activated K+ channels by nanomolar concentrations of Ag+.
Zhou Y, Xia X, Lingle CJ.
Mol Pharmacol. 2010 Nov;78(5):952-60. doi: 10.1124/mol.110.066407. Epub 2010 Aug 20.

Glycine311, a determinant of paxilline block in BK channels: a novel bend in the BK S6 helix.
Zhou Y, Tang QY, Xia XM, Lingle CJ.
J Gen Physiol. 2010 May;135(5):481-94. doi: 10.1085/jgp.201010403.

Block of mouse Slo1 and Slo3 K+ channels by CTX, IbTX, TEA, 4-AP and quinidine.
Tang QY, Zhang Z, Xia XM, Lingle CJ.
Channels (Austin). 2010 Jan-Feb;4(1):22-41. doi: 10.4161/chan.4.1.10481. Epub 2010 Jan 2.

Closed-channel block of BK potassium channels by bbTBA requires partial activation.
Tang QY, Zeng XH, Lingle CJ.
J Gen Physiol. 2009 Nov;134(5):409-36. doi: 10.1085/jgp.200910251.

Differential regulation of action potentials by inactivating and noninactivating BK channels in rat adrenal chromaffin cells.
Sun L, Xiong Y, Zeng X, Wu Y, Pan N, Lingle CJ, Qu A, Ding J.
Biophys J. 2009 Oct 7;97(7):1832-42. doi: 10.1016/j.bpj.2009.06.042.

Interactions between beta subunits of the KCNMB family and Slo3: beta4 selectively modulates Slo3 expression and function.
Yang CT, Zeng XH, Xia XM, Lingle CJ.
PLoS One. 2009 Jul 3;4(7):e6135. doi: 10.1371/journal.pone.0006135.

N-terminal inactivation domains of beta subunits are protected from trypsin digestion by binding within the antechamber of BK channels.
Zhang Z, Zeng XH, Xia XM, Lingle CJ.
J Gen Physiol. 2009 Mar;133(3):263-82. doi: 10.1085/jgp.200810079.

Species-specific Differences among KCNMB3 BK beta3 auxiliary subunits: some beta3 N-terminal variants may be primate-specific subunits.
Zeng X, Xia XM, Lingle CJ.
J Gen Physiol. 2008 Jul;132(1):115-29. doi: 10.1085/jgp.200809969.

Mg2+-dependent regulation of BK channels: importance of electrostatics.
Lingle CJ.
J Gen Physiol. 2008 Jan;131(1):5-11. doi: 10.1085/jgp.200709937.

BK channels with beta3a subunits generate use-dependent slow afterhyperpolarizing currents by an inactivation-coupled mechanism.
Zeng XH, Benzinger GR, Xia XM, Lingle CJ.
J Neurosci. 2007 Apr 25;27(17):4707-15. doi: 10.1523/JNEUROSCI.0758-07.2007.

Gating rings formed by RCK domains: keys to gate opening.
Lingle CJ.
J Gen Physiol. 2007 Feb;129(2):101-7. doi: 10.1085/jgp.200709739.

A limited access compartment between the pore domain and cytosolic domain of the BK channel.
Zhang Z, Zhou Y, Ding JP, Xia XM, Lingle CJ.
J Neurosci. 2006 Nov 15;26(46):11833-43. doi: 10.1523/JNEUROSCI.3812-06.2006.

Slo3 K+ channels: voltage and pH dependence of macroscopic currents.
Zhang X, Zeng X, Lingle CJ.
J Gen Physiol. 2006 Sep;128(3):317-36. doi: 10.1085/jgp.200609552.

pH-regulated Slo3 K+ channels: properties of unitary currents.
Zhang X, Zeng X, Xia XM, Lingle CJ.
J Gen Physiol. 2006 Sep;128(3):301-15. doi: 10.1085/jgp.200609551.

Empirical considerations regarding the use of ensemble-variance analysis of macroscopic currents.
Lingle CJ.
J Neurosci Methods. 2006 Nov 15;158(1):121-32. doi: 10.1016/j.jneumeth.2006.05.027. Epub 2006 Jun 30.

Direct observation of a preinactivated, open state in BK channels with beta2 subunits.
Benzinger GR, Xia XM, Lingle CJ.
J Gen Physiol. 2006 Feb;127(2):119-31. doi: 10.1085/jgp.200509425. Epub 2006 Jan 17.

Activation of GPCRs modulates quantal size in chromaffin cells through G(betagamma) and PKC.
Chen XK, Wang LC, Zhou Y, Cai Q, Prakriya M, Duan KL, Sheng ZH, Lingle C, Zhou Z.
Nat Neurosci. 2005 Sep;8(9):1160-8. doi: 10.1038/nn1529. Epub 2005 Aug 21.

Divalent cation sensitivity of BK channel activation supports the existence of three distinct binding sites.
Zeng XH, Xia XM, Lingle CJ.
J Gen Physiol. 2005 Mar;125(3):273-86. doi: 10.1085/jgp.200409239.

Ligand-dependent activation of Slo family channels is defined by interchangeable cytosolic domains.
Xia XM, Zhang X, Lingle CJ.
J Neurosci. 2004 Jun 16;24(24):5585-91. doi: 10.1523/JNEUROSCI.1296-04.2004.

Redox-sensitive extracellular gates formed by auxiliary beta subunits of calcium-activated potassium channels.
Zeng XH, Xia XM, Lingle CJ.
Nat Struct Biol. 2003 Jun;10(6):448-54. doi: 10.1038/nsb932.

Inactivation of BK channels by the NH2 terminus of the beta2 auxiliary subunit: an essential role of a terminal peptide segment of three hydrophobic residues.
Xia XM, Ding JP, Lingle CJ.
J Gen Physiol. 2003 Feb;121(2):125-48. doi: 10.1085/jgp.20028667.

Setting the stage for molecular dissection of the regulatory components of BK channels.
Lingle CJ.
J Gen Physiol. 2002 Sep;120(3):261-5. doi: 10.1085/jgp.20028689.

Multiple regulatory sites in large-conductance calcium-activated potassium channels.
Xia XM, Zeng X, Lingle CJ.
Nature. 2002 Aug 22;418(6900):880-4. doi: 10.1038/nature00956.

Earlier publications from Lingle Lab…