Src-kinase-dependent epidermal growth factor receptor transactivation in salivary mucin secretion in response to beta-adrenergic G-protein-coupled receptor activation.
The principal regulatory factors that control the flow and make-up of salivary secretion are neurotransmitters, released by parasympathetic and sympathetic innervation, that trigger activation of G protein-coupled receptors (GPCRs) on the acinar cells of salivary glands and stimulate the generation of soluble second messengers. In this study, we report that activation of GPCR by beta-adrenergic agonist leading to stimulation in salivary mucin secretion occurs with the involvement of epidermal growth factor receptor (EGFR). Using [(3)H]glucosamine-labeled mucous acinar cells of sublingual salivary gland in culture, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on mucin secretion was inhibited in a concentration-dependent manner by EGFR kinase inhibitor, PD153035, as well as wortmannin, an inhibitor of PI3K. Moreover, both inhibitors caused the impedance in the acinar cell mucin secretory responses to beta-adrenergic agonist-generated second messenger, cAMP, as well as adenylate cyclase activator, forskolin. The acinar cell secretory responses to isoproterenol, furthermore, were blunted in a concentration-dependent fashion by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR autophosphorylation. However, no significant alterations in the acinar cell mucin secretory responses to isoproterenol, cAMP or forskolin were attained with an inhibitor of the ERK pathway, PD98059. Our findings underline the role of EGFR as a convergence point in modulation of salivary mucin secretion triggered by beta-adrenergic agonist GPCR activation and demonstrate the importance of Src kinase in the EGFR transactivation process.
Slomiany
Bronislaw L
BL
Research Center, Room C875, University of Medicine and Dentistry of New Jersey, 110 Bergen Street, Newark, NJ 07103-2400, USA. slomiabr@umdnj.edu
Slomiany
Amalia
A
D000818:Animals; D000242:Cyclic AMP / Q000502:physiology; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D009077:Mucins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D012463:Saliva / Q000378:metabolism*; D015533:Transcriptional Activation; D019061:src-Family Kinases / Q000502:physiology*
D009077:Mucins; D011943:Receptors, Adrenergic, beta; D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D019061:src-Family Kinases; D007545:Isoproterenol