Shank2 mutant mice display a hypersecretory response to cholera toxin.
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.
Department of Pharmacology, Yonsei University College of Medicine, 134 Sinchon-Dong, Seoul 120-752, Korea. mlee@yuhs.ac.
Eun Suk
ES
Jung
Joonhee
J
Park
Heon Yung
HY
Gee
Jinsei
J
Jung
Shin Hye
SH
Noh
Jung-Soo
JS
Lee
Wito
W
Richter
Wan
W
Namkung
Min Goo
MG
Lee
D000818:Animals; D002712:Chlorides / Q000378:metabolism; D002772:Cholera Toxin / Q000494:pharmacology*; D003106:Colon / Q000166:cytology / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors / Q000378:metabolism; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D017136:Ion Transport; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012007:Rectum / Q000166:cytology / Q000378:metabolism
D002712:Chlorides; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; C488222:Shank2 protein, mouse; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D002772:Cholera Toxin; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4