Gap junctions are ubiquitous intercellular channels that play very important roles in development and physiology. However, little is known about proteins that may interact with and modulate gap junctions. Invertebrate systems could be used to identify evolutionarily conserved gap junction modulators because major structural features and functional properties are conserved between invertebrate and vertebrate gap junctions. In C. elegans, independent loss-of-function mutations of the genes unc-7, unc-9, unc-1, and unc-24 cause similar phenotypes, including locomotion defects and altered sensitivity to volatile anesthetics. unc-7 and unc-9 encode innexins, which are gap junction proteins, whereas unc-1 and unc-24 encode stomatin-like proteins. It is unknown why dysfunctions of the innexins and stomatin-like proteins cause similar phenotypes. The purpose of this proposal is to test the hypothesis that UNC-1 and UNC-24 are modulators of gap junctions.
The specific aims are (1) to explore molecular basis for interactions between UNC-9 and stomatin-like proteins, (2) to determine whether UNC-1 and UNC-24 interact with the carboxyl terminus of UNC-9 to modulate gap junction gating, and (3) to determine whether UNC-1, UNC-24, UNC-7, and UNC-9 interact in neurons to modulate locomotion. A variety of electrophysiological, genetic, and cell biological approaches will be used to analyze interactions among these proteins in C. elegans as well as in a mammalian heterologous expression system. The long term goals of this project are to understand evolutionarily conserved mechanisms of gap junction regulation and to identify candidate drug targets for treatment and management of gap junction-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM083049-05
Application #
8324230
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Deatherage, James F
Project Start
2008-09-01
Project End
2014-02-28
Budget Start
2012-09-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$290,110
Indirect Cost
$94,090
Name
University of Connecticut
Department
Neurosciences
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
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; 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
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
Altun, Zeynep F; Chen, Bojun; Wang, Zhao-Weng et al. (2009) High resolution map of Caenorhabditis elegans gap junction proteins. Dev Dyn 238:1936-50

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