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1D-ADRENERGIC RECEPTORS ON SHEDDING OF BIOLOGICALLY ACTIVE EGF IN FRESHLY ISOLATED LACRIMAL GLAND EPITHELIAL CELLS
1 Schepens Eye Research Institute, Boston, Massachusetts, United States; Ophthalmology, Harvard Modical School, Boston, Massachusetts, United States
2 Tufts University School of Dental Medicine, Boston, Massachusetts, United States
3 Lerner Research Institute, Cleveland, Ohio, United States
* To whom correspondence should be addressed. E-mail: hodges{at}vision.eri.harvard.edu.
Transactivation of EGF receptors by G-protein coupled receptors is a well-known phenomenon. This process involves the ectodomain shedding of growth factors in the EGF family by matrix metalloproteinases. However, many of these studies employ transformed and/or cultured cells that overexpress labeled growth factors. In addition, few studies have shown that EGF itself is the growth factor that is shed and is responsible for transactivation of the EGF receptor. In this study, we show that freshly isolated, non-transformed lacrimal gland acini express two of the three known 
1-adrenergic receptors (ARs), namely 1B- and 1D-ARs. 1D-ARs mediate phenylephrine (an 1-adrenergic agonist)-induced protein secretion and activation of p42/p44 MAPK because the 1D-AR inhibitor BMY-7378, but not the 1A-AR inhibitor 5-methylurapidil, inhibits these processes. Activation of p42/p44 MAPK occurs through transactivation of the EGF receptor, which is inhibited by the matrix metalloproteinase ADAM17 inhibitor TAPI-1. In addition, phenylephrine caused the shedding of EGF from freshly isolated acini into the buffer. Incubation of freshly isolated cells with conditioned buffer from cells treated with phenylephrine resulted in activation of the EGF receptor and p42/p44 MAPK. The EGF receptor inhibitor AG1478 and an EGF-neutralizing antibody blocked this activation of p42/p44 MAPK. We conclude that in freshly isolated lacrimal gland acini, 1-adrenergic agonists activate the 1D-AR to stimulate protein secretion and the ectodomain shedding of EGF to transactivate the EGF receptor, potentially via ADAM17, which activates p42/p44 MAPK to negatively modulate protein secretion.
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