Zusammenfassung
Multiple events are associated with the regulation of signaling by
the M2 muscarinic cholinergic receptors (mAChRs). Desensitization
of the attenuation of adenylyl cyclase by the M2 mAChRs appears to
involve agonist-dependent phosphorylation of M2 mAChRs by G-protein
coupled receptor kinases (GRKs) that phosphorylate the receptors
in a serine/threonine rich motif in the 3rd intracellular domain
of the receptors. Mutation of residues 307-311 from TVSTS to AVAAA
in this domain of the human M2 mAChR results in a loss of receptor/G-protein
uncoupling and a loss of arrestin binding. Agonist-induced sequestration
of receptors away from their normal membrane environment is also
regulated by agonist-induced phosphorylation of the M2 mAChRs on
the 3rd intracellular domain, but in HEK cells, the predominant pathway
of internalization is not regulated by GRKs or arrestins. This pathway
of internalization is not inhibited by a dominant negative dynamin,
and does not appear to involve either clathrin coated pits or caveolae.
The signaling of the M2 mAChR to G-protein regulated inwardly rectifying
K channels (GIRKs) can be modified by RGS proteins. In HEK cells,
expression of RGS proteins leads to a constitutive activation of
the channels through a mechanism that depends on Gbetagamma. RGS
proteins appear to increase the concentration of free Gbetagamma
in addition to acting as GAPs. Thus multiple mechanisms acting at
either the level of the M2 mAChRs or the G-proteins can contribute
to the regulation of signaling via the M2 mAChRs.
Nutzer