CaMKIIalpha interacts with M4 muscarinic receptors to control receptor and psychomotor function.
Muscarinic acetylcholine receptors (mAChRs) are widely expressed in the mammalian brain and are essential for neuronal functions. These receptors are believed to be actively regulated by intracellular signals, although the underlying mechanisms are largely unknown. In this study, we show that Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) binds directly and selectively to one of five mAChR subtypes, M4 receptors (M4Rs), at their C-terminal regions of second intracellular loops. This binding relies on Ca(2+) activation of the kinase and leads to the phosphorylation of M4Rs at a specific threonine site (Thr145). Complementary in vivo studies in rat striatal neurons enriched with M4Rs confirm that rising Ca(2+) recruits CaMKIIalpha to M4Rs to potentiate receptor signalling, which controls behavioural sensitivity to dopamine stimulation in an activity-dependent manner. Our data identify a new model of protein-protein interactions. In a Ca(2+)-sensitive manner, CaMKIIalpha regulates M4R efficacy and controls the acetylcholine-dopamine balance in the basal ganglia and also the dynamics of movement.
Guo
Ming-Lei
ML
Department of Basic Medical Science, University of Missouri-Kansas City, Kansas City, MO, USA.
Fibuch
Eugene E
EE
Liu
Xian-Yu
XY
Choe
Eun Sang
ES
Buch
Shilpa
S
Mao
Li-Min
LM
Wang
John Q
JQ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000502:physiology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects; D009474:Neurons / Q000502:physiology; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D051381:Rats; D043588:Receptor, Muscarinic M4 / Q000378:metabolism*
D018765:Dopamine Uptake Inhibitors; D043588:Receptor, Muscarinic M4; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003042:Cocaine; D002118:Calcium
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