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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Membrane Biology and Protein Processing (MBPP)
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Hagan, Ann A
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University of Connecticut
Schools of Medicine
United States
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Liu, Ping; Chen, Bojun; Wang, Zhao-Wen (2013) Postsynaptic current bursts instruct action potential firing at a graded synapse. Nat Commun 4:1911
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
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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

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