Modulation of M4 muscarinic acetylcholine receptors by interacting proteins.
Protein-protein interactions represent an important mechanism for posttranslational modifications of protein expression and function. In brain cells, surface-expressed and membrane-bound neurotransmitter receptors are common proteins that undergo dynamic protein-protein interactions between their intracellular domains and submembranous regulatory proteins. Recently, the Gα(i/o)-coupled muscarinic M4 receptor (M4R) has been revealed to be one of these receptors. Through direct interaction with the intracellular loops or C-terminal tails of M4Rs, M4R interacting proteins (M4RIPs) vigorously regulate the efficacy of M4R signaling. A synapse-enriched protein kinase, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), exemplifies a prototype model of M4RIPs, and is capable of binding to the second intracellular loop of M4Rs. Through an activity- and phosphorylation-dependent mechanism, CaMKII potentiates the M4R/Gα(i/o)-mediated inhibition of M4R efficacy in inhibiting adenylyl cyclase and cAMP production. In striatal neurons where M4Rs are most abundantly expressed, M4RIPs dynamically control M4R activity to maintain a proper cholinergic tone in these neurons. This is critical for maintaining the acetylcholine-dopamine balance in the basal ganglia, which determines the behavioral responsiveness to dopamine stimulation by psychostimulants.
Department of Basic Medical Science, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA. wangjq@umkc.edu
Ming-Lei
ML
Guo
Li-Min
LM
Mao
John Q
JQ
Wang
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D043588:Receptor, Muscarinic M4 / Q000378:metabolism*; D015398:Signal Transduction
D043588:Receptor, Muscarinic M4; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2