한빛사논문
- 조회3,259
Abstract
Seonghee Park1,2, Nikolay Shcheynikov1, Jeong Hee Hong1, Changyu Zheng1, Suk Hyo Suh2, Katsuhiro Kawaai3, Hideaki Ando3, Akihiro Mizutani4, Takaya Abe5, Hiroshi Kiyonari5, George Seki6, David Yule7, Katsuhiko Mikoshiba3, Shmuel Muallem1,*
1Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institute of Health, Bethesda MD, 20892
2Department of Physiology, School of Medicine, Ewha Womans University, 911-1 Mok-6-dong, Yang Chun-gu, Seoul 158-710, Republic of Korea
3Laboratory for Developmental Neurobiology, Brain Science Institute, Institute of Physical and Chemical Research (RIKEN), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
4Department of Pharmacotherapeutics, Showa Pharmaceutical University, 3-3165 Higashi-tamagawagakuen, Machida, Tokyo 194-8543
5Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, 2-2-3 Minatojima Minami,Chuou-ku, Kobe 650-0047
6Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8635, Japan
7Department of Pharmacology & Physiology, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY, USA
*Correspondence: Shmuel Muallem
Abstract
Background & Aims
The cAMP and Ca2+ signaling pathways synergize to regulate many physiological functions. However, little is known about the mechanisms by which these pathways interact. We investigated the synergy between these signaling pathways in mouse pancreatic and salivary gland ducts.
Methods
We created mice with disruptions in genes encoding the solute carrier family 26, member 6 (Slc26a6-/-mice) and inositol 1,4,5-triphosphate (InsP3) receptor-binding protein released with InsP3 (Irbit-/- mice). We investigated fluid secretion by sealed pancreatic ducts and the function of Slc26a6 and the cystic fibrosis transmembrane conductance regulator (CFTR) in HeLa cells and in ducts isolated from mouse pancreatic and salivary glands. Slc26a6 activity was assayed by measuring intracellular pH, and CFTR activity by measuring Cl- current. Protein interactions were determined by immunoprecipitation analyses.
Results
Irbit mediated the synergistic activation of CFTR and Slc26a6 by Ca2+ and cAMP. In resting cells, Irbit was sequestered by InsP3 receptors (IP3Rs) in the endoplasmic reticulum. Stimulation of Gs-coupled receptors led to phosphorylation of IP3Rs, which increased their affinity for InsP3 and reduced their affinity for Irbit. Subsequent weak stimulation of Gq-coupled receptors, which led to production of low levels of IP3, caused dissociation of Irbit from IP3Rs and allowed translocation of Irbit to CFTR and Slc26a6 in the plasma membrane. These processes stimulated epithelial secretion of electrolytes and fluid. These pathways were not observed in pancreatic and salivary glands from Irbit-/- or Slc26a6-/- mice, or in salivary gland ducts expressing mutant forms of IP3Rs that could not undergo protein kinase A-mediated phosphorylation.
Conclusions
Irbit promotes synergy between the Ca2+ and cAMP signaling pathways in cultured cells and in pancreatic and salivary ducts from mice. Defects in this pathway could be involved in CF, pancreatitis, or Sjogren's syndrome.
Keywords: signal transduction , ion and water secretion , fluid , electrolyte
논문정보
- Research article
- 2013년 04월 (BRIC 등록일 2013-04-04)
- 국내+국외 연구진
- 의약학 > 분자세포의학
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