Modulation of airway smooth muscle β-adrenoceptor function by a muscarinic agonist

Abstract

We have investigated the effect of a muscarinic agonist and protein kinase C (PKC) activation on β-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 4β-phorbol 12β-myristate 13α-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, 4α-phorbol 12,13-didecanoate which does not activate PKC had no effect on β-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 β-receptors in airway smooth muscle. We suggest that this mechanism may be relevant to the reduction in β-receptor coupling in asthmatic airways as an effect of PKC activation by inflammatory mediators and neurotransmitters.