C1C anion channels are found in virtually all organisms. While the functions of most identified CICs are obscure, the presence of CIC genes in widely divergent organisms and the existence of disease-causing CIC mutations in humans and other mammals indicate that the channels play important physiological roles. C. elegans offers significant experimental advantages for characterizing CIC anion channel biology. We have demonstrated that C. elegans oocytes express a mammalian CIC-2 channel ortholog encoded by clh-3, one of six nematode C1C genes. CLH-3 is activated by swelling, but plays no role in oocyte volume control. Volume sensitivity appears to link channel activity to oocyte growth and development. In full-grown oocytes undergoing rneiotic maturation, CLH-3 is constitutively activated. Oocyte maturation induces ovulatory contractions of electrically-coupled sheath cells. RNA interference of clh-3 expression disrupts the timing of sheath contractions indicating that the channel modulates ovulation via oocyte-sheath cell intercellular signaling pathways. CLH-3 thus functions as a cell cycle sensor to ensure synchronization of maturation with ovulation and fertilization. The central focus of this proposal is to identify CLH-3 regulatory mechanisms and define the role of the channel in cell-to-cell signaling pathways. Specifically, we will characterize the roles of oocyte growth, oocyte cell cycle progression and fertilization in regulating CLH-3 activity, test the hypothesis that cell cycle-dependent kinases regulate CLH-3, and test the hypothesis that CLR-3 modulates sheath cell Ca2+ signaling pathways via depolarization of oocyte and sheath cell membrane potential. Results of these studies have significant implications for understanding human physiology and pathophysiology. Proposed investigations will continue to broaden our understanding of C1C-2 specifically, and of C1C anion channels in general. Such understanding is essential in order to identify the functions of C1C channels, their regulatory mechanisms, and their potential as therapeutic targets for diseases such as cystic fibrosis. In addition, our studies will likely provide new insights into the fundamental problems of oocyte development, oocyte cell cycle control, cell-to-cell communication mechanisms, and agonist-induced smooth muscle contraction and regulation.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
General Medicine B Study Section (GMB)
Program Officer
Ketchum, Christian J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
Schools of Medicine
United States
Zip Code
Rochester, Jesse D; Tanner, Paige C; Sharp, Catherine S et al. (2017) PQN-75 is expressed in the pharyngeal gland cells of Caenorhabditiselegans and is dispensable for germline development. Biol Open 6:1355-1363
Wu, Cheng-Wei; Deonarine, Andrew; Przybysz, Aaron et al. (2016) The Skp1 Homologs SKR-1/2 Are Required for the Caenorhabditis elegans SKN-1 Antioxidant/Detoxification Response Independently of p38 MAPK. PLoS Genet 12:e1006361
Lee, Elaine C; Kim, Heejung; Ditano, Jennifer et al. (2016) Abnormal Osmotic Avoidance Behavior in C. elegans Is Associated with Increased Hypertonic Stress Resistance and Improved Proteostasis. PLoS One 11:e0154156
Strange, Kevin (2016) Drug Discovery in Fish, Flies, and Worms. ILAR J 57:133-143
Kim, Heejung; Strange, Kevin (2013) Changes in translation rate modulate stress-induced damage of diverse proteins. Am J Physiol Cell Physiol 305:C1257-64
Lee, Elaine Choung-Hee; Strange, Kevin (2012) GCN-2 dependent inhibition of protein synthesis activates osmosensitive gene transcription via WNK and Ste20 kinase signaling. Am J Physiol Cell Physiol 303:C1269-77
Strange, Kevin; Yin, Viravuth P (2012) Rhythmic Ca²? signaling: keeping time with microRNAs. Curr Biol 22:R1000-1
Burkewitz, Kristopher; Choe, Keith P; Lee, Elaine Choung-Hee et al. (2012) Characterization of the proteostasis roles of glycerol accumulation, protein degradation and protein synthesis during osmotic stress in C. elegans. PLoS One 7:e34153
Burkewitz, Kris; Choe, Keith; Strange, Kevin (2011) Hypertonic stress induces rapid and widespread protein damage in C. elegans. Am J Physiol Cell Physiol 301:C566-76
Strange, Kevin (2011) Cell physiology at the Mount Desert Island Biological Laboratory: a brief look back and forward. Am J Physiol Cell Physiol 300:C1-5

Showing the most recent 10 out of 30 publications