MODULATION OF AIRWAY SMOOTH-MUSCLE BETA-ADRENOCEPTOR FUNCTION BY A MUSCARINIC AGONIST

We have investigated the effect of a muscarinic agonist and protein ki nase C (PKC) activation on beta-adrenoceptors and their coupling to ad enylyl cyclase in bovine tracheal smooth muscle. There was a significa nt reduction in maximum binding capacity of [I-125]iodocyanopindolol ( [I-125]ICYP) after exposure to carbachol and 4beta-phorbol 12beta-myri state 13alpha-acetate (PMA). Similarly both carbachol and PMA inhibite d the 5'-guanylylimidodiphosphate-induced shift in [I-125]ICYP binding by isoproterenol and significantly decreased isoproterenol-induced cy clic AMP accumulation. A phorbol ester, 4alpha-phorbol 12,13-didecanoa te 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 l ead to reduction and uncoupling of beta-receptors in airway smooth mus cle. We suggest that this mechanism may be relevant to the reduction i n beta-receptor coupling in asthmatic airways as an effect of PKC acti vation by inflammatory mediators and neurotransmitters.