Novel signalling events mediated by muscarinic receptor subtypes.
The M2 muscarinic acetylcholine receptor (mAChR) activates Gi protein coupled pathways, such as stimulation of G-protein activated inwardly rectifying K channels (GIRKs). Here we report a novel heterologous desensitization of these GIRK currents, which appeared to be specifically induced by M2/M4 mAChR stimulation, but not via adenosine (Ado) and alpha2-adrenergic receptors (AR). This heterologous desensitization reflected an inhibition of the GIRK signalling pathway downstream of G-protein activation. It was mediated in a membrane-delimited fashion via a PTX insensitive GTP dependent pathway and could be competed with exogenous Gbetagamma. The activation of M3 mAChR/Gq coupled receptors potently inhibited GIRK currents similar as M2 mAChR. By monitoring simultaneously the response of A1 adenosine receptor (AdoR) activation on N-type Ca2+ channels and GIRK channels, the stimulation of M3 mAChR was found to cause an inhibition of the Ado response in both effector systems, suggesting that the inhibition occurred at the level of the G-protein common to both effectors. These results indicated that Gq proteins inhibit pathways that are commonly regulated by Gbetagamma proteins.
Bünemann
M
M
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, IL 60611, USA. m-buenemann@toxi.uni-wuerzburg.de
Hosey
M M
MM
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D020864:Calcium Channels, N-Type / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D043588:Receptor, Muscarinic M4; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection
D020864:Calcium Channels, N-Type; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D043588:Receptor, Muscarinic M4; D011976:Receptors, Muscarinic; D018047:Receptors, Purinergic P1; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D020962:Heterotrimeric GTP-Binding Proteins; D000109:Acetylcholine