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. 2010 Dec 7;26(6):469–473. doi: 10.1007/s12264-010-0933-0

Modulation of M4 muscarinic acetylcholine receptors by interacting proteins

蛋白的相互作用调节M4 乙酰胆碱受体的功能

Ming-Lei Guo 1, Li-Min Mao 1, John Q Wang 1,2,✉
PMCID: PMC3139403  NIHMSID: NIHMS307817  PMID: 21113197

Abstract

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 Gαi/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, Ca2+/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/Gαi/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.

Keywords: striatum, Ca2+/calmodulin-dependent protein kinase II, dopamine, kinase, phosphorylation, cocaine

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