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JNK mitogen-activated protein kinase limits calcium-dependent chloride secretion across colonic epithelial cells.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Donnellan, Fergal Keating, Niamh Geoghegan, Paul Murray, Frank E. Harvey, Brian J. Keely, Stephen J. |
| Copyright Year | 2010 |
| Abstract | Neuroimmune agonists induce epithelial Cl(-) secretion through elevations in intracellular Ca2+ or cAMP. Previously, we demonstrated that epidermal growth factor receptor (EGFR) transactivation and subsequent ERK MAPK activation limits secretory responses to Ca2+-dependent, but not cAMP-dependent, agonists. Although JNK MAPKs are also expressed in epithelial cells, their role in regulating transport function is unknown. Here, we investigated the potential role for JNK in regulating Cl(-) secretion in T(84) colonic epithelial cells. Western blot analysis revealed that a prototypical Ca2+-dependent secretagogue, carbachol (CCh; 100 microM), induced phosphorylation of both the 46-kDa and 54-kDa isoforms of JNK. This effect was mimicked by thapsigargin (TG), which specifically elevates intracellular Ca2+, but not by forskolin (FSK; 10 microM), which elevates cAMP. CCh-induced JNK phosphorylation was attenuated by the EGFR inhibitor, tyrphostin-AG1478 (1 microM). Pretreatment of voltage-clamped T(84) cells with SP600125 (2 microM), a specific JNK inhibitor, potentiated secretory responses to both CCh and TG but not to FSK. The effects of SP600125 on CCh-induced secretion were not additive with those of the ERK inhibitor, PD98059. Finally, in apically permeabilized T(84) cell monolayers, SP600125 potentiated CCh-induced K+ conductances but not Na+/K+ATPase activity. These data demonstrate a novel role for JNK MAPK in regulating Ca2+ but not cAMP-dependent epithelial Cl(-) secretion. JNK activation is mediated by EGFR transactivation and exerts its antisecretory effects through inhibition of basolateral K+ channels. These data further our understanding of mechanisms regulating epithelial secretion and underscore the potential for exploitation of MAPK-dependent signaling in treatment of intestinal transport disorders. |
| Starting Page | 397 |
| Ending Page | 406 |
| Page Count | 10 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://ajpgi.physiology.org/content/ajpgi/298/1/G37.full.pdf |
| PubMed reference number | 19875701v1 |
| Alternate Webpage(s) | https://doi.org/10.1152/ajpgi.00202.2009 |
| DOI | 10.1152/ajpgi.00202.2009 |
| Journal | American journal of physiology. Gastrointestinal and liver physiology |
| Volume Number | 298 |
| Issue Number | 1 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | 8-chloro-cyclic adenosine monophosphate Calcium ion Carbachol Cell secretion Colforsin Colon structure (body structure) Columnar Cell Hyperplasia of the Breast EGFR protein, human Growth Factor Receptors Intestinal Diseases Mitogen-Activated Protein Kinases Mitogens PD 98059 Potassium Protein Isoforms SP600125 Thapsigargin Trans-Activation, Genetic Tyrphostins tyrphostin AG 1478 voltage |
| Content Type | Text |
| Resource Type | Article |
