The calcium and voltage regulated BK-type K+ channel encoded by the Slo1 gene is a widely expressed ion channel impacting on regulation of excitability in a variety of tissues. Diversity in function of the BK channel arises from tissue-specific expression of up to four different auxiliary b subunits (b1-b4) and a newly identified family of g subunits. b1 and b4 subunits have been implicated in hypertension and epilepsy, respectively, and other indications suggest that BK channels may be therapeutic targets in stroke, hypertension, epilepsy, and tumor growth regulation. Of auxiliary subunits, little is known about physiological roles of b2 and b3 subunits, both of which produce use- dependent changes in BK currents and even less is known about g subunits. In this project, mechanisms of use-dependent regulation of BK currents by b2 and b3 subunits will be examined. Furthermore, the consequences of assembly of multiple kinds of auxiliary (both b and g) subunits into single channels will be tested and the rules governing b and g subunit coassembly in BK channels determined. This project is expected to provide mechanistic and physiological insight into the role of two major regulators of BK channels, the b2 and b3 subunits and new insight into the role of g subunits.

Public Health Relevance

The calcium and voltage regulated BK-type K+ channel is a widely expressed ion channel impacting on regulation of electrical excitability in a variety of tissues and consequently spawning considerable interest in BK channels as therapeutic targets in asthma, epilepsy, stroke, hypertension, and tumor-cell growth. Any effective therapeutic intervention depends on knowledge about the functional properties, composition, and functional diversity of the molecular targets and it is well-known that the composition of subunits contributing to BK channels plays an important role in defining tissue-specific BK channel properties. This project will advance our understanding of the potential role of BK channels in normal physiology and as a therapeutic target by providing mechanistic and physiological insight into the role of three major regulators of BK channels, the b2 and b3 auxiliary subunits and the g1 auxiliary subunit.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM081748-17A1
Application #
8372151
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Deatherage, James F
Project Start
1993-05-21
Project End
2016-05-31
Budget Start
2012-09-28
Budget End
2013-05-31
Support Year
17
Fiscal Year
2012
Total Cost
$455,253
Indirect Cost
$135,253
Name
Washington University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Gonzalez-Perez, Vivian; Xia, Xiao-Ming; Lingle, Christopher J (2014) Functional regulation of BK potassium channels by ?1 auxiliary subunits. Proc Natl Acad Sci U S A 111:4868-73
Brenker, Christoph; Zhou, Yu; Müller, Astrid et al. (2014) The Ca2+-activated K+ current of human sperm is mediated by Slo3. Elife 3:e01438
Zeng, Xu-Hui; Navarro, Betsy; Xia, Xiao-Ming et al. (2013) Simultaneous knockout of Slo3 and CatSper1 abolishes all alkalization- and voltage-activated current in mouse spermatozoa. J Gen Physiol 142:305-13
Ajith Karunarathne, W K; O'Neill, Patrick R; Martinez-Espinosa, Pedro L et al. (2012) All G protein ?? complexes are capable of translocation on receptor activation. Biochem Biophys Res Commun 421:605-11
Gonzalez-Perez, Vivian; Zeng, Xu-Hui; Henzler-Wildman, Katie et al. (2012) Stereospecific binding of a disordered peptide segment mediates BK channel inactivation. Nature 485:133-6
Borchert, Gudrun H; Yang, Chengtao; Kolar, Frantisek (2011) Mitochondrial BKCa channels contribute to protection of cardiomyocytes isolated from chronically hypoxic rats. Am J Physiol Heart Circ Physiol 300:H507-13
Yang, Chengtao; Zeng, Xu-Hui; Zhou, Yu et al. (2011) LRRC52 (leucine-rich-repeat-containing protein 52), a testis-specific auxiliary subunit of the alkalization-activated Slo3 channel. Proc Natl Acad Sci U S A 108:19419-24
Zeng, Xu-Hui; Yang, Chengtao; Kim, Sung Tae et al. (2011) Deletion of the Slo3 gene abolishes alkalization-activated K+ current in mouse spermatozoa. Proc Natl Acad Sci U S A 108:5879-84
Zhang, Zhe; Zeng, Xu-Hui; Xia, Xiao-Ming et al. (2009) N-terminal inactivation domains of beta subunits are protected from trypsin digestion by binding within the antechamber of BK channels. J Gen Physiol 133:263-82
Yang, Cheng-Tao; Zeng, Xu-Hui; Xia, Xiao-Ming et al. (2009) Interactions between beta subunits of the KCNMB family and Slo3: beta4 selectively modulates Slo3 expression and function. PLoS One 4:e6135

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