CaMKIIα, a modulator of M4 muscarinic acetylcholine receptors

Abstract

G protein-coupled receptors (GPCRs) are subject to the regulation by protein kinases. By controlling the phosphorylation-dephosphorylation balance, protein kinases actively modify GPCR expression and function. In a recent study, we have identified a novel phosphorylation-dependent regulation of Gαi/o-coupled muscarinic acetylcholine receptors. A synapse-enriched protein kinase, Ca²⁺/calmodulin-dependent protein kinase II (CaMKIIα), binds directly and selectively to second intracellular loops of muscarinic M4 receptors (M4Rs). This Ca²⁺-sensitive binding enables CaMKIIα to phosphorylate M4Rs at a selective threonine residue. In rat striatal neurons which abundantly express M4Rs, rapid cytoplasmic Ca²⁺ rises enhance the association of CaMKIIα with M4Rs and increase threonine phosphorylation of the receptor. This CaMKIIα-mediated phosphorylation results in a potentiation of M4R activity, which is critical for controlling cellular and behavioral responsivity to dopamine stimulation. In sum, our data identify a novel kinase-GPCR interaction. Through a Ca²⁺/activity-sensitive manner, CaMKIIα contributes to maintaining acetylcholine-dopamine homeostasis in the basal ganglia.

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Acknowledgements

This work was supported by NIH grants DA10355 (J.Q.W.) and MH61469 (J.Q.W.) and by a grant from Saint Luke's Hospital Foundation.

Figures and Tables

Figure 1 A model of CamKII-M4R interactions linking Ca²⁺ to M4Rs. Synergistic activation of M4Rs by an intracellular mechanism involving the Ca²⁺-regulated CamKII association with M4Rs potentiates the efficacy of M4Rs in inhibiting cAMP signaling. Ca²⁺ activates CaMKII to increase its binding to the C-terminal region of the second intracellular loop of M4Rs (M4R_IL2). This enhances the inhibitory tone of M4Rs on cAMP responses to dopamine. Other abbreviations: AC, adenylyl cyclase; CaM, calmodulin; DA, dopamine; PKA, cAMP-dependent protein kinase A.

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