Epidermal growth factor upregulates beta-adrenergic receptor signaling in a human salivary cell line.
The effects of epidermal growth factor (EGF) on the beta-adrenergic receptor-coupled adenylyl cyclase system were studied in a human salivary cell line (HSY). The beta-adrenergic agonist isoproterenol (10(-5) M) stimulated adenylyl cyclase activity by approximately 2-fold, and the isoproterenol response was increased 1.8-fold after prolonged (48 h) exposure to EGF (5 x 10(-10) 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. beta-Adrenergic receptor density, assessed by binding of the beta-adrenergic receptor antagonist (-)-[(125)I]iodopindolol, was increased threefold after EGF treatment. Competition binding studies with unlabeled antagonists selective for beta(1)- and beta(2)-adrenergic receptor subtypes indicated that the increase in (-)-[(125)I]iodopindolol binding sites induced by EGF reflected an increased number of beta(2)-adrenergic receptors. Likewise, Northern blot analysis of RNA from EGF-treated cells revealed selective induction of beta(2)-adrenergic receptor mRNA, which was blocked by the RNA synthesis inhibitor actinomycin D. The increase in beta-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 beta-adrenergic responsiveness by upregulating beta(2)-adrenergic receptor expression at the transcriptional level. Moreover, the stimulatory effect of EGF on beta(2)-adrenergic receptor signaling appears to be mediated by the MAPK pathway and independent of PKC activation.
Yeh
Chih-Ko
CK
Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care Center, San Antonio 78229-4404, USA.
Hymer
Tazuko K
TK
Sousa
April L
AL
Zhang
Bin-Xian
BX
Lifschitz
Meyer D
MD
Katz
Michael S
MS
D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D002460:Cell Line; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012469:Salivary Glands / Q000166:cytology / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; D000262:Adenylyl Cyclases; D007545:Isoproterenol