Modulation of β2- and β3-adrenoceptor-mediated relaxation of rat oesophagus smooth muscle by protein kinase C

Although a prominent role for protein kinase C (PKC) in the cross-talk between the phosphoinositide pathway and beta(2)-adrenoceptor signalling has been indicated, modulation of beta(3)-adrenoceptor function by PKC has not been studied thus far. In the present study, we have compared the relative capacity of PKC in modulating beta(2)- and beta(3)-adrenoceptor-mediated relaxation of methacholine-contracted rat oesophagus smooth muscle. To this purpose the effects of the PKC-inhibitor GF 109203X (2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide) on relaxation induced by fenoterol, formoterol, (-)-noradrenaline, BRL 35135 (4-[2-[(2-hydroxy-2-(chlorophenyl)ethyl)amino] -propyl] -phenoxyacetic-acidmethyl ester) and IBMX (3-isobutyl-1-methyl-xanthine) were studied, in the absence and presence of the selective beta(2)-adrenoceptor antagonist ICI 118,551 (erythro-1(7-methylindan-4-yloxy)-3-(isopropylamin)-butan-2-ol). Our results show that inhibition of PKC resulted in differential augmentation of both beta(2)- and beta(3)-adrenoceptor-mediated relaxation. In contrast, relaxation induced by IBMX was not influenced at all by GF 109203K The beta(2)-adrenoceptor bears phosphorylation sites for several kinases, including PKC. Since the beta(3)-adrenoceptor lacks these consensus sites, the results may also indicate that PKC-mediated Galpha(s) phosphorylation is involved in the cross-talk between the muscarinic receptor-mediated phosphoinositide pathway and beta(2)- and, particularly, beta(3)-adrenoceptor signalling. (C) 2004 Elsevier B.V. All rights reserved.