Irbit mediates synergy between Ca2+ and cAMP signaling pathways during epithelial transport in mice

Seonghee Park, Nikolay Shcheynikov, Jeong Hee Hong, Changyu Zheng, Suk Hyo Suh, Katsuhiro Kawaai, Hideaki Ando, Akihiro Mizutani, Takaya Abe, Hiroshi Kiyonari, George Seki, David Yule, Katsuhiko Mikoshiba, Shmuel Muallem

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Background & Aims: The cyclic adenosine monophosphate (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 was assayed 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 (IP 3Rs) 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 cystic fibrosis, pancreatitis, or Sjögren syndrome.

Original languageEnglish
Pages (from-to)232-241
Number of pages10
JournalGastroenterology
Volume145
Issue number1
DOIs
Publication statusPublished - 2013 Jan 1
Externally publishedYes

Fingerprint

Cyclic AMP
Cystic Fibrosis Transmembrane Conductance Regulator
Salivary Ducts
Salivary Glands
Fluids and Secretions
Pancreatic Ducts
Phosphorylation
Cyclic AMP-Dependent Protein Kinases
HeLa Cells
Immunoprecipitation
Cystic Fibrosis
Endoplasmic Reticulum
Pancreatitis
Electrolytes
Cultured Cells
Cell Membrane
Genes
Proteins

Keywords

  • Electrolyte
  • Fluid
  • Ion and Water Secretion
  • Signal Transduction

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Park, S., Shcheynikov, N., Hong, J. H., Zheng, C., Suh, S. H., Kawaai, K., ... Muallem, S. (2013). Irbit mediates synergy between Ca2+ and cAMP signaling pathways during epithelial transport in mice. Gastroenterology, 145(1), 232-241. https://doi.org/10.1053/j.gastro.2013.03.047

Irbit mediates synergy between Ca2+ and cAMP signaling pathways during epithelial transport in mice. / Park, Seonghee; Shcheynikov, Nikolay; Hong, Jeong Hee; Zheng, Changyu; Suh, Suk Hyo; Kawaai, Katsuhiro; Ando, Hideaki; Mizutani, Akihiro; Abe, Takaya; Kiyonari, Hiroshi; Seki, George; Yule, David; Mikoshiba, Katsuhiko; Muallem, Shmuel.

In: Gastroenterology, Vol. 145, No. 1, 01.01.2013, p. 232-241.

Research output: Contribution to journalArticle

Park, S, Shcheynikov, N, Hong, JH, Zheng, C, Suh, SH, Kawaai, K, Ando, H, Mizutani, A, Abe, T, Kiyonari, H, Seki, G, Yule, D, Mikoshiba, K & Muallem, S 2013, 'Irbit mediates synergy between Ca2+ and cAMP signaling pathways during epithelial transport in mice', Gastroenterology, vol. 145, no. 1, pp. 232-241. https://doi.org/10.1053/j.gastro.2013.03.047
Park, Seonghee ; Shcheynikov, Nikolay ; Hong, Jeong Hee ; Zheng, Changyu ; Suh, Suk Hyo ; Kawaai, Katsuhiro ; Ando, Hideaki ; Mizutani, Akihiro ; Abe, Takaya ; Kiyonari, Hiroshi ; Seki, George ; Yule, David ; Mikoshiba, Katsuhiko ; Muallem, Shmuel. / Irbit mediates synergy between Ca2+ and cAMP signaling pathways during epithelial transport in mice. In: Gastroenterology. 2013 ; Vol. 145, No. 1. pp. 232-241.
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AU - Shcheynikov, Nikolay

AU - Hong, Jeong Hee

AU - Zheng, Changyu

AU - Suh, Suk Hyo

AU - Kawaai, Katsuhiro

AU - Ando, Hideaki

AU - Mizutani, Akihiro

AU - Abe, Takaya

AU - Kiyonari, Hiroshi

AU - Seki, George

AU - Yule, David

AU - Mikoshiba, Katsuhiko

AU - Muallem, Shmuel

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