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Shank2 mutant mice display a hypersecretory response to cholera toxin

Authors
 Eun Suk Jung  ;  Joonhee Park  ;  Heon Yung Gee  ;  Jinsei Jung  ;  Shin Hye Noh  ;  Jung‐Soo Lee  ;  Wito Richter  ;  Wan Namkung  ;  Min Goo Lee 
Citation
 JOURNAL OF PHYSIOLOGY-LONDON, Vol.592(8) : 1809-1821, 2014 
Journal Title
JOURNAL OF PHYSIOLOGY-LONDON
ISSN
 0022-3751 
Issue Date
2014
MeSH
Animals ; Chlorides/metabolism ; Cholera Toxin/pharmacology* ; Colon/cytology ; Colon/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism ; Cystic Fibrosis Transmembrane Conductance Regulator/antagonists & inhibitors ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; HEK293 Cells ; Homeostasis ; Humans ; Intestinal Mucosa/drug effects ; Intestinal Mucosa/metabolism* ; Intestinal Mucosa/secretion ; Ion Transport ; Mice ; Mutation* ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism* ; Protein Binding ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; Rectum/cytology ; Rectum/metabolism
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.
Full Text
http://jp.physoc.org/content/592/8/1809.long
DOI
10.1113/jphysiol.2013.268631
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Noh, Shin Hye(노신혜) ORCID logo https://orcid.org/0000-0003-3118-9240
Park, Joonhee(박준희)
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
Lee, Jung Soo(이정수)
Jung, Eun Suk(정은석)
Jung, Jinsei(정진세) ORCID logo https://orcid.org/0000-0003-1906-6969
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/98842
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