BK channels are almost ubiquitously expressed and perform many important physiological functions. Dysfunction of the channel causes a variety of diseases, including epilepsy, progressive hearing loss, cerebellar ataxia, and hypertension. The function of BK channels depends on proper subcellular localization and interactions with auxiliary or regulatory proteins. However, the molecular basis of BK channel subcellular localization is unknown and only limited knowledge exists about BK channel auxiliary/regulatory proteins. The powerful molecular genetics of C. elegans is explored to identify proteins important to BK channel function or subcellular localization. In preliminary studies, mutants of three genes (named as bkip-1, bkip-2 and bkip-3) were isolated as suppressors of a lethargic phenotype caused by expressing a gain-of-function (gf) isoform of SLO-1, the C. elegans BK channel. Phenotypes of these mutants included increased neurotransmitter release (bkip-1) and SLO-1 mislocalization (bkip-2 and bkip-3). bkip-1 and bkip-2 were found to encode novel BK channel- interacting proteins whereas bkip-3 remains to be identified. BKIP-1 showed several effects on SLO-1 functional properties when analyzed in a heterologous expression system. This proposal is to test the hypotheses that the three BKIPs are important to SLO-1 function and/or subcellular localization in vivo and that there are other functionally related proteins in C. elegans.
The specific aims of this proposal are: (1) determine how BKIP-1 regulates SLO-1 function;(2) determine how BKIP-2 and BKIP-3 control SLO-1 subcellular localization and/or function, and (3) isolate and identify additional mutants that suppress the lethargic phenotype caused by SLO-1(gf), which will be analyzed in future studies. The long-term goal is to elucidate the molecular basis of BK channel function and subcellular localization.

Public Health Relevance

Mutations of the BK channel cause a variety of diseases, including epilepsy, hypertension, progressive hearing loss, cerebellar ataxia, overactive bladder, penile erectile dysfunction, impaired renal glomerular filtration and K+ excretion, and paroxysmal dyskinesia. The proposed research program may identify novel proteins that are important to BK channel function and/or subcellular localization in vivo. Such information is potentially of great value to understanding the molecular bases of BK channel-related diseases, and to identifying candidate pharmacological targets for the treatment and management of these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH085927-05
Application #
8585099
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Asanuma, Chiiko
Project Start
2009-12-01
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
5
Fiscal Year
2014
Total Cost
$274,428
Indirect Cost
$96,228
Name
University of Connecticut
Department
Neurosciences
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
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Wang, Sijie Jason; Wang, Zhao-Wen (2013) Track-a-worm, an open-source system for quantitative assessment of C. elegans locomotory and bending behavior. PLoS One 8:e69653
Liu, Ping; Chen, Bojun; Wang, Zhao-Wen (2013) Postsynaptic current bursts instruct action potential firing at a graded synapse. Nat Commun 4:1911
Liu, Ping; Chen, Bojun; Altun, Zeynep F et al. (2013) Six innexins contribute to electrical coupling of C. elegans body-wall muscle. PLoS One 8:e76877
Chen, Bojun; Liu, Ping; Zhan, Haiying et al. (2011) Dystrobrevin controls neurotransmitter release and muscle Ca(2+) transients by localizing BK channels in Caenorhabditis elegans. J Neurosci 31:17338-47
Liu, Ping; Chen, Bojun; Wang, Zhao-Wen (2011) Gap junctions synchronize action potentials and Ca2+ transients in Caenorhabditis elegans body wall muscle. J Biol Chem 286:44285-93
Liu, Ping; Ge, Qian; Chen, Bojun et al. (2011) Genetic dissection of ion currents underlying all-or-none action potentials in C. elegans body-wall muscle cells. J Physiol 589:101-17
Chen, Bojun; Ge, Qian; Xia, Xiao-Ming et al. (2010) A novel auxiliary subunit critical to BK channel function in Caenorhabditis elegans. J Neurosci 30:16651-61
Wang, Zhao-Wen (2010) Origin of quantal size variation and high-frequency miniature postsynaptic currents at the Caenorhabditis elegans neuromuscular junction. J Neurosci Res 88:3425-32
Chen, Bojun; Liu, Ping; Wang, Sijie J et al. (2010) ýý-Catulin CTN-1 is required for BK channel subcellular localization in C. elegans body-wall muscle cells. EMBO J 29:3184-95