Modulation of beta2- and beta3-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 beta2-adrenoceptor signalling has been indicated, modulation of beta3-adrenoceptor function by PKC has not been studied thus far. In the present study, we have compared the relative capacity of PKC in modulating beta2- and beta3-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-acidmethylester) and IBMX (3-isobutyl-1-methyl-xanthine) were studied, in the absence and presence of the selective beta2-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 beta2- and beta3-adrenoceptor-mediated relaxation. In contrast, relaxation induced by IBMX was not influenced at all by GF 109203X. The beta2-adrenoceptor bears phosphorylation sites for several kinases, including PKC. Since the beta3-adrenoceptor lacks these consensus sites, the results may also indicate that PKC-mediated Galphas phosphorylation is involved in the cross-talk between the muscarinic receptor-mediated phosphoinositide pathway and beta2- and, particularly, beta3-adrenoceptor signalling.
Oostendorp
Jaap
J
Department of Molecular Pharmacology, University Centre for Pharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen 9713 AV, The Netherlands. j.oostendorp@farm.rug.nl
Obels
Peter Ph
PP
Terpstra
A Rene
AR
Nelemans
S Adriaan
SA
Zaagsma
Johan
J
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004947:Esophagus / Q000473:pathology*; D004983:Ethanolamines / Q000494:pharmacology; D005280:Fenoterol / Q000494:pharmacology; D000068759:Formoterol Fumarate; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D016210:Methacholine Chloride / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000473:pathology*; D009426:Netherlands; D010627:Phenethylamines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000502:physiology*; D022702:Receptors, Adrenergic, beta-3 / Q000187:drug effects / Q000502:physiology*
D004983:Ethanolamines; D007211:Indoles; D008301:Maleimides; D010627:Phenethylamines; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3; D016210:Methacholine Chloride; D005280:Fenoterol; C063157:BRL 35135; D011493:Protein Kinase C; C070515:bisindolylmaleimide I; D015056:1-Methyl-3-isobutylxanthine; D000068759:Formoterol Fumarate