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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 
 Journal of Physiology, Vol.592(8) : 1809-1821, 2014 
Journal Title
 Journal of Physiology 
Issue Date
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.
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1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
노신혜(Noh, Shin Hye)
박준희(Park, Joonhee)
이민구(Lee, Min Goo) ORCID logo https://orcid.org/0000-0001-7436-012X
이정수(Lee, Jung Soo)
정은석(Jung, Eun Suk)
정진세(Jung, Jinsei) ORCID logo https://orcid.org/0000-0003-1906-6969
지헌영(Gee, Heon Yung) ORCID logo https://orcid.org/0000-0002-8741-6177
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