epidermal growth factor (EGF) on the -adrenergic receptor-coupled adenylyl cyclase system were studied in a human salivary cell line (HSY). The -adrenergic agonist isoproterenol (10 Ϫ5 M) stimulated adenylyl cyclase activity by ϳ2-fold, and the isoproterenol response was increased 1.8-fold after prolonged (48 h) exposure to EGF (5 ϫ 10 Ϫ10 M). In contrast, enzyme activation via stimulatory prostaglandin receptors and by agents acting on nonreceptor components of the adenylyl cyclase system was not enhanced by EGF. -Adrenergic receptor density, assessed by binding of the -adrenergic receptor antagonist (Ϫ)-[125 I]iodopindolol, was increased threefold after EGF treatment. Competition binding studies with unlabeled antagonists selective for 1-and 2-adrenergic receptor subtypes indicated that the increase in (Ϫ)-[ 125 I]iodopindolol binding sites induced by EGF reflected an increased number of 2-adrenergic receptors. Likewise, Northern blot analysis of RNA from EGF-treated cells revealed selective induction of 2-adrenergic receptor mRNA, which was blocked by the RNA synthesis inhibitor actinomycin D. The increase in -adrenergic receptor density produced by EGF was unaltered after phorbol ester-induced downregulation of protein kinase C (PKC). Enhancement of isoproterenol-responsive adenylyl cyclase activity and phosphorylation of mitogen-activated protein kinase (MAPK) by EGF were both blocked by the MAPK pathway inhibitor PD-98059. The results suggest that in HSY cells EGF enhances -adrenergic responsiveness by upregulating 2-adrenergic receptor expression at the transcriptional level. Moreover, the stimulatory effect of EGF on 2-adrenergic receptor signaling appears to be mediated by the MAPK pathway and independent of PKC activation. adenylyl cyclase; G protein-coupled receptor; signal transduction; mitogen-activated protein kinase; protein kinase C SALIVARY GLAND FUNCTION is tightly regulated by the autonomic nervous system through the actions of neurotransmitters on G protein-coupled receptor signaling pathways (3). In general, cholinergic-muscarinic and ␣-adrenergic receptor agonists induce secretion of salivary fluid and electrolytes via activation of the intracellular calcium ([Ca 2ϩ ] i ) cascade (3). On the other hand, -adrenergic receptor agonists stimulate the secretion of salivary proteins by activation of adenylyl cyclase and the generation of intracellular cAMP (3). Stimulation of the -adrenergic receptor-coupled adenylyl cyclase pathway also causes transcriptional and posttranslational modifications of salivary gland proteins (52). In vivo, the -adrenergic agonist isoproterenol has been demonstrated to induce hypertrophy and hyperplasia of salivary glands (10, 50). In a number of cell types, -adrenergic receptor activation of adenylyl cyclase is modulated by systemic hormones as well as local growth factors and cytokines (21,29,51,54). Whether similar modulation of -adrenergic receptor signaling might play a regulatory role in salivary cell secretion and growth has not been well ch...
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