Abstract
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.
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