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Am J Physiol Cell Physiol 284: C988-C998, 2003. First published December 21, 2002; doi:10.1152/ajpcell.00582.2001
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Vol. 284, Issue 4, C988-C998, April 2003

Cholinergic agonists transactivate EGFR and stimulate MAPK to induce goblet cell secretion

Harumi Kanno1,2,*, Yoshitaka Horikawa1,2,*, Robin R. Hodges1, Driss Zoukhri1, Marie A. Shatos1, Jose D. Rios1, and Darlene A. Dartt1

1 Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114; and 2 Department of Ophthalmology, Asahikawa Medical College, Asahikawa, Japan 078-8510

Conjunctival goblet cells are the primary source of mucins in the mucous layer, the innermost layer of the tear film. Conjunctival goblet cell mucin secretion is under neural control because exogenous addition of parasympathetic agonists stimulates goblet cell secretion. To elucidate the intracellular signal pathways used by cholinergic agonists to stimulate goblet cell mucin secretion, we determined whether p42/p44 mitogen-activated protein kinase (MAPK) is activated during cholinergic agonist-stimulated mucin secretion. Rat conjunctiva was removed, preincubated with or without antagonists, and stimulated with the cholinergic agonist carbachol (10-4 M). Carbachol statistically significantly stimulated the phosphorylation of MAPK in a time- and concentration-dependent manner. U-0126, an inhibitor of MAPK activation, completely inhibited both the activation of MAPK and goblet cell secretion stimulated by carbachol. The M1 muscarinic antagonist pirenzepine, the M2 muscarinic antagonist gallamine, and the M1/M3 muscarinic receptor antagonist N-(3-chloropropyl)-4-piperidinyl diphenylacetate (4-DAMP) also inhibited carbachol-stimulated MAPK activation. Increasing the intracellular Ca2+ concentration with a Ca2+ ionophore increased MAPK activation, and chelation of extracellular Ca2+ inhibited carbachol-stimulated activation. Carbachol also increased tyrosine phosphorylation of Pyk2, p60Src, and the epidermal growth factor receptor (EGFR). The Src inhibitor PP1 and the EGFR inhibitor AG-1478 completely inhibited carbachol-stimulated MAPK activation. AG-1478 also inhibited goblet cell secretion. We conclude that carbachol transactivates the EGFR to activate MAPK, leading to conjunctival goblet cell secretion. In addition, carbachol also activates Pyk2 and p60Src that could play a role in the transactivation of the EGFR.

signal transduction; muscarinic receptors; conjunctiva; Pyk2; p60Src

* H. Kanno and Y. Horikawa contributed equally to this work.




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