Regulation of STREX Exon Large Conductance, Calcium-activated Potassium Channels by the Beta4 Accessory Subunit

Overview

Journal Neuroscience

Specialty Neurology

Date 2007 Oct 20

PMID 17945424

Citations 24

Authors

D Petrik

R Brenner

Affiliations

Soon will be listed here.

Abstract

Large conductance (BK-type) calcium-activated potassium channels utilize alternative splicing and association with accessory beta subunits to tailor BK channel properties to diverse cell types. Two important modulators of BK channel gating are the neuronal-specific beta4 accessory subunit (beta4) and alternative splicing at the stress axis hormone-regulated exon (STREX). Individually, these modulators affect the gating properties of the BK channel as well as its response to phosphorylation. In this study, the combined functional consequences of STREX and the mouse beta4 subunit on mouse BK channel biophysical properties were investigated in transfected HEK 293 cells. Surprisingly, we found that the combined effects of STREX and beta4 are non-additive and even opposite for some properties. At high calcium, beta4 and the STREX individually share properties that promote BK channel opening via slowing of deactivation. However, the combined effects are a speeding of deactivation and a decreased open probability. beta4 also inhibits BK channel opening by a slowing of activation. This effect occurs across calcium concentrations in the absence of STREX, but predominates only at low calcium for STREX containing channels. BK channel responses to phosphorylation status are also altered by the combination of the beta4 subunit and STREX. beta4/STREX channels show a slowing of activation kinetics following dephosphorylation whereas beta4 channels lacking STREX do not. In contrast, beta4 confers a speeding of activation in response to cyclic AMP-dependent phosphorylation in channels lacking STREX, but not in channels containing STREX. These results indicate that the combination of the beta4 subunit and STREX confers non-additive and unique properties to BK channels. Analysis of expression in brain slices suggests that STREX and beta4 mRNA overlap expression in the dentate gyrus of the hippocampus and the cerebellar Purkinje cells, suggesting that these unique properties of BK channels may underlie BK channel gating in these cells.

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References

Wang B, Brenner R . An S6 mutation in BK channels reveals beta1 subunit effects on intrinsic and voltage-dependent gating. J Gen Physiol. 2006; 128(6):731-44. PMC: 2151602. DOI: 10.1085/jgp.200609596. View

Orio P, Latorre R . Differential effects of beta 1 and beta 2 subunits on BK channel activity. J Gen Physiol. 2005; 125(4):395-411. PMC: 2217511. DOI: 10.1085/jgp.200409236. View

Shao L, Halvorsrud R, Storm J . The role of BK-type Ca2+-dependent K+ channels in spike broadening during repetitive firing in rat hippocampal pyramidal cells. J Physiol. 1999; 521 Pt 1:135-46. PMC: 2269638. DOI: 10.1111/j.1469-7793.1999.00135.x. View

Fodor A, Aldrich R . Statistical limits to the identification of ion channel domains by sequence similarity. J Gen Physiol. 2006; 127(6):755-66. PMC: 2151544. DOI: 10.1085/jgp.200509419. View

McManus O, Helms L, Pallanck L, Ganetzky B, Swanson R, Leonard R . Functional role of the beta subunit of high conductance calcium-activated potassium channels. Neuron. 1995; 14(3):645-50. DOI: 10.1016/0896-6273(95)90321-6. View

Orio P, Torres Y, Rojas P, Carvacho I, Garcia M, Toro L . Structural determinants for functional coupling between the beta and alpha subunits in the Ca2+-activated K+ (BK) channel. J Gen Physiol. 2006; 127(2):191-204. PMC: 2151488. DOI: 10.1085/jgp.200509370. View

Weiger T, Hermann A, Levitan I . Modulation of calcium-activated potassium channels. J Comp Physiol A Neuroethol Sens Neural Behav Physiol. 2002; 188(2):79-87. DOI: 10.1007/s00359-002-0281-2. View

Macdonald S, Ruth P, Knaus H, Shipston M . Increased large conductance calcium-activated potassium (BK) channel expression accompanied by STREX variant downregulation in the developing mouse CNS. BMC Dev Biol. 2006; 6:37. PMC: 1562363. DOI: 10.1186/1471-213X-6-37. View

Schreiber M, Salkoff L . A novel calcium-sensing domain in the BK channel. Biophys J. 1997; 73(3):1355-63. PMC: 1181035. DOI: 10.1016/S0006-3495(97)78168-2. View

10.

Weiger T, Holmqvist M, Levitan I, Clark F, Sprague S, Huang W . A novel nervous system beta subunit that downregulates human large conductance calcium-dependent potassium channels. J Neurosci. 2000; 20(10):3563-70. PMC: 6772688. View

11.

Erxleben C, Everhart A, Romeo C, Florance H, Bauer M, Alcorta D . Interacting effects of N-terminal variation and strex exon splicing on slo potassium channel regulation by calcium, phosphorylation, and oxidation. J Biol Chem. 2002; 277(30):27045-52. DOI: 10.1074/jbc.M203087200. View

12.

Reinhart P, Chung S, Levitan I . A family of calcium-dependent potassium channels from rat brain. Neuron. 1989; 2(1):1031-41. DOI: 10.1016/0896-6273(89)90227-4. View

13.

Shi J, Krishnamoorthy G, Yang Y, Hu L, Chaturvedi N, Harilal D . Mechanism of magnesium activation of calcium-activated potassium channels. Nature. 2002; 418(6900):876-80. DOI: 10.1038/nature00941. View

14.

Fettiplace R, Fuchs P . Mechanisms of hair cell tuning. Annu Rev Physiol. 1999; 61:809-34. DOI: 10.1146/annurev.physiol.61.1.809. View

15.

Chen L, Tian L, Macdonald S, McClafferty H, Hammond M, Huibant J . Functionally diverse complement of large conductance calcium- and voltage-activated potassium channel (BK) alpha-subunits generated from a single site of splicing. J Biol Chem. 2005; 280(39):33599-609. DOI: 10.1074/jbc.M505383200. View

16.

Xia X, Zeng X, Lingle C . Multiple regulatory sites in large-conductance calcium-activated potassium channels. Nature. 2002; 418(6900):880-4. DOI: 10.1038/nature00956. View

17.

Lu R, Alioua A, Kumar Y, Eghbali M, Stefani E, Toro L . MaxiK channel partners: physiological impact. J Physiol. 2005; 570(Pt 1):65-72. PMC: 1464300. DOI: 10.1113/jphysiol.2005.098913. View

18.

Raffaelli G, Saviane C, Mohajerani M, Pedarzani P, Cherubini E . BK potassium channels control transmitter release at CA3-CA3 synapses in the rat hippocampus. J Physiol. 2004; 557(Pt 1):147-57. PMC: 1665041. DOI: 10.1113/jphysiol.2004.062661. View

19.

Shipston M . Alternative splicing of potassium channels: a dynamic switch of cellular excitability. Trends Cell Biol. 2001; 11(9):353-8. DOI: 10.1016/s0962-8924(01)02068-2. View

20.

Diez-Sampedro A, Silverman W, Bautista J, Richerson G . Mechanism of increased open probability by a mutation of the BK channel. J Neurophysiol. 2006; 96(3):1507-16. DOI: 10.1152/jn.00461.2006. View