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.
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.
|Lingle, Christopher J (2015) NAVigating a transition from single action potential firing to bursting in chromaffin cells. J Physiol 593:761-2|
|Zeng, Xu-Hui; Yang, Chengtao; Xia, Xiao-Ming et al. (2015) SLO3 auxiliary subunit LRRC52 controls gating of sperm KSPER currents and is critical for normal fertility. Proc Natl Acad Sci U S A 112:2599-604|
|Martinez-Espinosa, Pedro L; Wu, Jianping; Yang, Chengtao et al. (2015) Knockout of Slo2.2 enhances itch, abolishes KNa current, and increases action potential firing frequency in DRG neurons. Elife 4:|
|Gonzalez-Perez, Vivian; Xia, Xiao-Ming; Lingle, Christopher J (2015) Two classes of regulatory subunits coassemble in the same BK channel and independently regulate gating. Nat Commun 6:8341|
|Brenker, Christoph; Zhou, Yu; Müller, Astrid et al. (2014) The Ca2+-activated K+ current of human sperm is mediated by Slo3. Elife 3:e01438|
|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|
|Martinez-Espinosa, Pedro L; Yang, Chengtao; Gonzalez-Perez, Vivian et al. (2014) Knockout of the BK ?2 subunit abolishes inactivation of BK currents in mouse adrenal chromaffin cells and results in slow-wave burst activity. J Gen Physiol 144:275-95|
|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|
|Zhou, Yu; Zeng, Xu-Hui; Lingle, Christopher J (2012) Barium ions selectively activate BK channels via the Ca2+-bowl site. Proc Natl Acad Sci U S A 109:11413-8|
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