Shank2 mutant mice display a hypersecretory response to cholera toxin

Eun Suk Jung, Joonhee Park, Heon Yung Gee, Jinsei Jung, Shin Hye Noh, Jung Soo Lee, Wito Richter, Wan Namkung, Min Goo Lee

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2 Citations (Scopus)

Abstract

Shank2 is a PDZ (PSD-95/discs large/ZO-1)-based adaptor that has been suggested to regulate membrane transporting proteins in the brain and epithelial tissues. Here, we report that Shank2 mutant (Shank2-/-) mice exhibit aberrant fluid and ion transport in the intestine. Molecular characterization using epithelial tissues from Shank2+/+ and Shank2-/- mice revealed that a long spliceoform of Shank2 (Shank2E) is predominantly expressed in the pancreatic, renal and intestinal epithelia. In functional assays, deletion of Shank2 increased the cystic fibrosis transmembrane conductance regulator (CFTR)-dependent short-circuit currents by 84% (P < 0.05) and 101% (P < 0.05) in the mouse colon and rectum, respectively. Disruption of the CFTR-Shank2-phosphodiesterase 4D protein complex appeared to be mostly responsible for the changes in CFTR activities. Notably, Shank2 deletion profoundly increased cholera toxin-induced fluid accumulation in the mouse intestine (~90%, P < 0.01). Analyses with chemical inhibitors confirmed that the hyperactivation of CFTR channel function is responsible for the increased response to cholera toxin. These results suggest that Shank2 is a key molecule that participates in epithelial homeostasis, in particular to prevent overt secretory responses caused by epithelial pathogens.

Original languageEnglish
Pages (from-to)1809-1821
Number of pages13
JournalJournal of Physiology
Volume592
Issue number8
DOIs
Publication statusPublished - 2014 Apr 15

All Science Journal Classification (ASJC) codes

  • Physiology

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    Jung, E. S., Park, J., Gee, H. Y., Jung, J., Noh, S. H., Lee, J. S., Richter, W., Namkung, W., & Lee, M. G. (2014). Shank2 mutant mice display a hypersecretory response to cholera toxin. Journal of Physiology, 592(8), 1809-1821. https://doi.org/10.1113/jphysiol.2013.268631