1. Muscarinic M(2) receptors normally inhibit the production of cyclic AMP via G(i) proteins, but a stimulatory component occurs in their effect at high agonist concentrations, believed to be based on the activation of G(s) proteins. We investigated the conditions which determine the occurrence and extent of the stimulatory component in CHO cells stably expressing muscarinic M(2) receptors. 2. Biphasic concentration-response curves (decline followed by return towards control values) were obtained after 10 min incubation with carbachol, oxotremorine-M, acetylcholine, arecoline and arecaidine propargyl ester, but the upward phase was missing with oxotremorine, methylfurmethide, furmethide and pentylthio-TZTP. Shortening the incubation favoured the occurrence of the stimulatory component. Carbachol (1 mM) and oxotremorine-M (1 mM) brought about net stimulation (above 100% of control) of cyclic AMP synthesis during 2 min incubations. The stimulatory components disappeared after the density of receptors had been lowered with oxyphenonium mustard. 3. All agonists stimulated the synthesis of cyclic AMP in cells pretreated with pertussis toxin. 4. Most differences between agonists regarding the stimulatory component of their effect on cyclic AMP synthesis could be explained by differences in their efficacy and the induced receptor internalization. 5. We propose that the G(s)-mediated stimulatory component of the effect of muscarinic M(2) receptors on cyclic AMP synthesis only occurs if the density of activated receptors is high enough to saturate the G(i) proteins and proportionate to the receptors' low affinity for the G(s) proteins. It tends to be abolished by receptor internalization.

• MeSH
• agonisté muskarinových receptorů farmakologie   MeSH
• AMP cyklický biosyntéza   MeSH
• antagonisté muskarinových receptorů farmakologie   MeSH
• časové faktory MeSH
• CHO buňky MeSH
• cholerový toxin farmakologie   MeSH
• cholinergní agonisté farmakologie   MeSH
• karbachol farmakologie   MeSH
• křečci praví MeSH
• lékové interakce MeSH
• lidé MeSH
• N-methylskopolamin farmakologie   MeSH
• oxyfenon farmakologie   MeSH
• proteiny vázající GTP - alfa-podjednotky Gi-Go metabolismus   MeSH
• proteiny vázající GTP - alfa-podjednotky Gs metabolismus   MeSH
• receptor muskarinový M2 MeSH
• receptory muskarinové účinky léků   metabolismus   MeSH
• transfekce MeSH
• tritium MeSH
• vazebná místa MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• agonisté muskarinových receptorů MeSH
• AMP cyklický MeSH
• antagonisté muskarinových receptorů MeSH
• cholerový toxin MeSH
• cholinergní agonisté MeSH
• karbachol MeSH
• N-methylskopolamin MeSH
• oxyfenon MeSH
• proteiny vázající GTP - alfa-podjednotky Gi-Go MeSH
• proteiny vázající GTP - alfa-podjednotky Gs MeSH
• receptor muskarinový M2 MeSH
• receptory muskarinové MeSH
• tritium MeSH