Modulation of airway smooth muscle beta-adrenoceptor function by a muscarinic agonist.
We have investigated the effect of a muscarinic agonist and protein kinase C (PKC) activation on beta-adrenoceptors and their coupling to adenylyl cyclase in bovine tracheal smooth muscle. There was a significant reduction in maximum binding capacity of [125I]iodocyanopindolol ([125I]ICYP) after exposure to carbachol and 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA). Similarly both carbachol and PMA inhibited the 5'-guanylylimidodiphosphate-induced shift in [125I]ICYP binding by isoproterenol and significantly decreased isoproterenol-induced cyclic AMP accumulation. A phorbol ester, 4 alpha-phorbol 12,13-didecanoate which does not activate PKC had no effect on beta-receptor binding or coupling. These results suggest that PKC activation directly via a phorbol ester and indirectly via muscarinic receptor stimulation may lead to reduction and uncoupling of beta-receptors in airway smooth muscle. We suggest that this mechanism may be relevant to the reduction in beta-receptor coupling in asthmatic airways as an effect of PKC activation by inflammatory mediators and neurotransmitters.
Grandordy
B M
BM
Department of Thoracic Medicine, National Heart and Lung Institute, London, UK.
Mak
J C
JC
Barnes
P J
PJ
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D002217:Carbachol / Q000494:pharmacology*; D002417:Cattle; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000378:metabolism; D007545:Isoproterenol / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure*; D011493:Protein Kinase C / Q000378:metabolism; D011869:Radioligand Assay; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure*
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D002217:Carbachol; D000242:Cyclic AMP; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D007545:Isoproterenol; D013755:Tetradecanoylphorbol Acetate