Metabotropic mGlu5 receptors regulate adenosine A _2A receptor signaling

Abstract

D opamine-and cAMP-regulated phosphoprotein of M r 32,000 (DARPP-32) is a signal transduction molecule that is selectively enriched in medium-sized spiny neurons in neostriatum, and plays an obligatory role in dopaminergic signaling. Mice lacking DARPP-32 exhibit profound deficits in their molecular, electrophysiological, and behavioral responses to dopamine, drugs of abuse and antipsychotic medication, demonstrating the importance of DARPP-32 in most of the actions of dopamine (1).When DARPP-32 is phosphorylated by cAMP-dependent protein kinase (PKA) on Thr-34, it is converted into a potent inhibitor of protein phosphatase-1, and thereby controls the phosphorylation state and activity of many downstream physiological effectors, including various neurotransmitter receptors and voltage-gated ion channels (for review, see ref.2). Phosphorylation and dephosphorylation of DARPP-32 at Thr-34 are regulated by dopamine, adenosine, glutamate, serotonin, and other neurotransmitters. For example, dopamine, by activating dopamine D1-type receptors (3), and adenosine, by activating adenosine A 2A receptors (4), stimulate the phosphorylation of DARPP-32 at Thr-34.Metabotropic glutamate (mGlu) receptors are subdivided into three groups on the basis of agonist pharmacology, sequence homology, and G-protein effector coupling: group I (mGlu1 and mGlu5 receptors), group II (mGlu2 and mGlu3 receptors), and group III (mGlu4, mGlu6, mGlu7, and mGlu8 receptors; ref. 5). Group I mGlu receptors are coupled to the phospholipase C (PLC) pathway (6), the extracellular signal-regulated kinase (ERK) pathway (7), and the p38 pathway (8); group II and III mGlu receptors are negatively coupled to adenylyl cyclase (9). Individual subtypes of mGlu receptors are assumed to mediate distinct facilitatory (group I) or inhibitory (group II and III) actions on neuronal transmission (10). Recently, mGlu receptors were shown to be involved in cocaine self-administration (11) and methamphetamine-induced neurotoxicity (12). However, the molecular mechanisms underlying the actions of mGlu receptors are not clearly understood. In this study, we investigated the regulation of DARPP-32 phosphorylation at Thr-34 by mGlu receptors by using neostriatal slices. The results obtained indicate that the actions of mGlu5 receptors are linked to A 2A adenosine receptors by means of a mechanism involving the ERK cascade.

ERK regulation of phosphodiesterase 4 enhances dopamine-stimulated AMPA receptor membrane insertion

“…Previous studies have demonstrated a positive role for ERK activity in the metabotropic glutamate mGlu5 receptor and adenosine A2A receptor stimulation of DARPP-32 Thr-34 phosphorylation (37). Here we present a mechanism that describes how ERK can modulate PKA activity.…”

Simultaneous Blockade of Adenosine A2A and Metabotropic Glutamate mGlu5 Receptors Increase their Efficacy in Reversing Parkinsonian Deficits in Rats

“…wt of 32 kDa), which has been shown to be abundantly expressed in all striatal medium spiny neurons (Walaas and Greengard, 1984;Ouimet et al, 1998) and to play an essential modulatory role in DA transmission (Fienberg et al, 1998). A coactivation of adenosine A 2A and mGlu 5 receptors has been recently revealed to be responsible of the synergistic potentiation of the state of phosphorylation of DARPP-32 (Nishi et al, 2003) and c-fos expression (Ferré et al, 2002) in striatal neurons. The functional cross talk that links mGlu 5 and A 2A receptors may therefore underlie the behavioral recovery observed in the present study.…”

“…New findings provide evidence that coactivation of A 2A and mGlu 5 receptors produce synergistic effect on DARPP-32 phosphorylation, a signal transduction molecule that is selectively enriched in medium-spiny striatal neurons (Nishi et al, 2003) and potentiate c-fos striatal expression (Ferré et al, 2002). However, the functional evidence of these positive interactions on specific motor deficits such as akinesia occurring early in the course of PD remains unknown.…”

Glutamate regulation of DARPP-32 phosphorylation in neostriatal neurons involves activation of multiple signaling cascades

“…Group I mGlu (mGlu1 and mGlu5) receptors preferentially activate a PLC signaling cascade but also are known to activate other signaling cascades (27). mGlu5 receptors directly interact with adenosine A 2A receptors (28) and potentiate adenosine A 2A -receptor signaling in an ERK-dependent manner in indirect pathway neurons (9). Furthermore, functions of mGlu1 and mGlu5 receptors are differentially regulated by PKC, G protein-coupled receptor kinase, regulator of G protein signaling, and Src-family protein tyrosine kinase (27,29).…”

“…Activation of NMDA and AMPA receptors decreases DARPP-32 phosphorylation at Thr-34 and Thr-75 through Ca 2ϩ -dependent activation of protein phosphatase-2B (PP-2B) (calcineurin) and protein phosphatase-2A (PP-2A), respectively (8). Activation of group I mGlu-5 (mGlu5) receptors increases DARPP-32 Thr-34 phosphorylation by potentiating cAMP formation coupled to adenosine A 2A receptors in an extracellular signal-regulated kinase (ERK)-dependent manner (9). Activation of group I mGlu receptors also increases DARPP-32 phosphorylation at Thr-75 as well as Ser-130 [casein kinase-1 (CK1)-site] (10).…”