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Insulin Activates Intestinal NHE3 via IRBIT
Author(s) -
He Peijian,
Yanda Murali,
Anitha Mallappa,
Srinivasan Shanthi,
Yun Chris
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1152.21
Subject(s) - gene knockdown , insulin , endocrinology , downregulation and upregulation , medicine , diabetes mellitus , stimulation , chemistry , microbiology and biotechnology , biology , gene , biochemistry
Diarrhea is a troublesome intestinal complication of diabetes. The estimates for the prevalence of diarrhea in diabetic patients reach more than 20%. The goal of this study is to determine whether the major intestinal Na+/H+ exchanger NHE3 contributes to diabetic diarrhea. We found that induction of diabetes by streptozotocin resulted in a significant decrease in NHE3 activity and retrieval of NHE3 from the plasma membrane into the cytoplasmic pool. Decreased NHE3 activity was partially restored with i.p. injection of insulin. Insulin acutely increased NHE3 activity in intestinal epithelial SK‐CO15 cells via a PI3K‐dependent mechanism. IRBIT, IP3 receptor‐binding protein released with IP3, mediates NHE3 activation by Ca2+ and angiotensin II. Knockdown of IRBIT markedly attenuated activation of NHE3 by insulin. We found that insulin induced mobility shift of IRBIT protein, indicating phosphorylation of IRBIT, and enhanced the interaction between NHE3 and IRBIT. IRBIT was found to interact with NHERF1 and knockdown of IRBIT decreased the NHE3‐NHERF1 association, suggesting that IRBIT mediate the interaction between NHE3 and NHERF1. In conclusion, IRBIT and NHERF1 are necessary for stimulation of NHE3 by insulin. (This study was supported by NIH grant DK060418)