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Group II metabotropic glutamate (mGlu) receptors (mGlu2/3) are Gαi/o-coupled receptors and are primarily located on presynaptic axonal terminals in the central nervous system. Like ionotropic glutamate receptors, group II mGlu receptors are subject to regulation by posttranslational phosphorylation. Pharmacological evidence suggests that several serine/threonine protein kinases possess the ability to regulate mGlu2/3 receptors. Detailed mapping of phosphorylation residues has revealed that protein kinase A (PKA) phosphorylates mGlu2/3 receptors at a specific serine site on their intracellular C-terminal tails in heterologous cells or neurons, which underlies physiological modulation of mGlu2/3 signaling. Casein kinases promote mGlu2 phosphorylation at a specific site. Tyrosine protein kinases also target group II receptors to induce robust phosphorylation. A protein phosphatase was found to specifically bind to mGlu3 receptors and dephosphorylate the receptor at a PKA-sensitive site. This review summarizes recent progress in research on group II receptor phosphorylation and the phosphorylation-dependent regulation of group II receptor functions. We further explore the potential linkage of mGlu2/3 phosphorylation to various neurological and neuropsychiatric disorders, and discuss future research aimed at analyzing novel biochemical and physiological properties of mGlu2/3 phosphorylation.

Abstract Objective The adenosine A1 receptor is a Gαi/o protein‐coupled receptor and inhibits upon activation cAMP formation and protein kinase A (PKA) activity. As a widely expressed receptor in the mammalian brain, A1 receptors are implicated in the modulation of a variety of neuronal and synaptic activities. In this study, we investigated the role of A1 receptors in the regulation of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors in the adult rat brain in vivo. Methods Adult male Wistar rats were used in this study. After a systemic injection of the A1 antagonist DPCPX, rats were sacrificed and several forebrain regions were collected for assessing changes in phosphorylation of AMPA receptors using Western blots. Results A systemic injection of the A1 antagonist DPCPX induced an increase in phosphorylation of AMPA receptor GluA1 subunits at a PKA‐dependent site, serine 845 (S845), in the two subdivisions of the striatum, the caudate putamen, and nucleus accumbens. DPCPX also increased S845 phosphorylation in the medial prefrontal cortex (mPFC) and hippocampus. The DPCPX‐stimulated S845 phosphorylation was a transient and reversible event. Blockade of Gαs/olf‐coupled dopamine D1 receptors with a D1 antagonist SCH23390 abolished the responses of S845 phosphorylation to DPCPX in the striatum, mPFC, and hippocampus. DPCPX had no significant impact on phosphorylation of GluA1 at serine 831 and on expression of total GluA1 proteins in all forebrain regions surveyed. Conclusion These data demonstrate that adenosine A1 receptors maintain an inhibitory tone on GluA1 S845 phosphorylation under normal conditions. Blocking this inhibitory tone leads to the upregulation of GluA1 S845 phosphorylation in the striatum, mPFC, and hippocampus via a D1‐dependent manner.

Group I metabotropic glutamate (mGlu) receptors (mGlu1/5 subtypes) are G protein-coupled receptors and are broadly expressed in the mammalian brain. These receptors play key roles in the modulation of normal glutamatergic transmission and synaptic plasticity, and abnormal mGlu1/5 signaling is linked to the pathogenesis and symptomatology of various mental and neurological disorders. Group I mGlu receptors are noticeably regulated via a mechanism involving dynamic protein–protein interactions. Several synaptic protein kinases were recently found to directly bind to the intracellular domains of mGlu1/5 receptors and phosphorylate the receptors at distinct amino acid residues. A variety of scaffolding and adaptor proteins also interact with mGlu1/5. Constitutive or activity-dependent interactions between mGlu1/5 and their interacting partners modulate trafficking, anchoring, and expression of the receptors. The mGlu1/5-associated proteins also finetune the efficacy of mGlu1/5 postreceptor signaling and mGlu1/5-mediated synaptic plasticity. This review analyzes the data from recent studies and provides an update on the biochemical and physiological properties of a set of proteins or molecules that interact with and thus regulate mGlu1/5 receptors.

Propofol is a commonly used general anesthetic agent which has been previously shown to enhance the inhibitory GABAergic transmission in the central nervous system. In addition to the GABAergic element, the excitatory transmission may be another central molecular site impacted by propofol. Increasing evidence implies that the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor represents an excitatory amino acid receptor subtype subjected to the regulation by propofol. Indeed, in this study, we found that a single injection of propofol at an anesthetic dose increased AMPA receptor GluA1 subunit phosphorylation in young (2-3 months old) and aged (20-21 months old) mice in vivo. Propofol caused an increase in GluA1 phosphorylation in the hippocampus but not in the prefrontal cortex. The propofol effect was also site-selective as the drug elevated GluA1 phosphorylation at serine 831 (S831) but not serine 845. Interestingly, while propofol induced a moderate and transient increase in S831 phosphorylation in young mice, the drug caused a substantial and sustained S831 phosphorylation in aged animals. Total GluA1 abundance remained stable in the hippocampus and prefrontal cortex in both young and aged mice in response to propofol. These results provide evidence supporting the sensitivity of GluA1 AMPA receptors to propofol. A single dose of propofol was able to upregulate GluA1 phosphorylation in the confined hippocampus in an age-dependent manner. [ABSTRACT FROM AUTHOR]

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 Ca2+/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 Ca2+ 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 Ca2+ recruits CaMKIIα 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 Ca2+-sensitive manner, CaMKIIα regulates M4R efficacy and controls the acetylcholine–dopamine balance in the basal ganglia and also the dynamics of movement. [ABSTRACT FROM AUTHOR]