NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin

Abstract

Previous reports have shown that activation of N-methyl-D-aspartate (NMDA) receptors potentiates responses to activation of the group I metabotropic glutamate receptor mGluR5 by reversing PKC-mediated desensitization of this receptor. NMDA-induced reversal of mGluR5 desensitization is dependent on activation of protein phosphatases. However, the specific protein phosphatase involved and the precise mechanism by which NMDA receptor activation reduces mGluR desensitization are not known. We have performed a series of molecular, biochemical, and genetic studies to show that NMDA-induced regulation of mGluR5 is dependent on activation of calcium-dependent protein phosphatase 2B/calcineurin (PP2B/CaN). Furthermore, we report that purified calcineurin directly dephosphorylates the C-terminal tail of mGluR5 at sites that are phosphorylated by PKC. Finally, immunoprecipitation and GST fusion protein pull-down experiments reveal that calcineurin interacts with mGluR5, suggesting that these proteins could be colocalized in a signaling complex. Taken together with previous studies, these data suggest that activation of NMDA receptors leads to activation of calcineurin and that calcineurin modulates mGluR5 function by directly dephosphorylating mGluR5 at PKC sites that are involved in desensitization of this receptor.

The Selective mGlu5 Receptor Antagonist MTEP, Similar to NMDA Receptor Antagonists, Induces Social Isolation in Rats

“…There are data showing that activation of NMDA receptors may lead to activation of calcineurin that in turn may modulate mGluR5 function by dephosphorylating mGluR5 at sites that are phosphorylated by PKC on the C-terminal tail of the receptor (Alagarsamy et al, 2005;Gereau and Heinemann, 1998). Moreover, it has been reported that a single administration of PCP in rats resulted in a decrease in the mGluR5 mRNA expression in the hippocampal formation and in a number of subcortical regions (Abe et al, 2001).…”

“…It has also been found that mGluR5 can modulate the NMDA receptor function at the molecular and cellular level (Awad et al, 2000;Brakeman et al, 1997;Doherty et al, 1997). Further, the opposite direction of this modulation has been reported as well, thereby suggesting a reciprocal positive-feedback interaction between these two receptor subtypes (Alagarsamy et al, 1999(Alagarsamy et al, , 2005Luthi et al, 1994). Importantly, at the behavioral level, antagonists of the mGluR5 have been found to potentiate the effects of NMDA receptor antagonists in several tests including prepulse inhibition (PPI) of the startle response, locomotor activity, memory tasks, and unilateral 6-OHDA-lesion model (Henry et al, 2002;Homayoun et al, 2004;Kinney et al, 2002;Turle-Lorenzo et al, 2005).…”

Neural functions of calcineurin in synaptic plasticity and memory: Figure 1.

“…By dephosphorylating the receptor, CaN can prolong its activity after glutamate release ( Fig. 1; Alagarsamy et al 2005). This effect of CaN is likely important for the induction of LTD, some forms of which rely on mGluR5 in the hippocampus (Camodeca et al 1999;Sung et al 2001;Huang and Hsu 2006;Naie et al 2007;Neyman and Manahan-Vaughan 2008).…”

Metabotropic glutamate receptor 5 binding and protein expression in schizophrenia and following antipsychotic drug treatment

“…Due to the global distribution and rapid synaptic transmission of the NMDAR, it is not suited as a therapeutic target as its effects are widely excitotoxic (Ellenbroek, 2012). However mGluR5 and NMDAR are connected by a scaffolding link (Tu et al, 1999) and are known to functionally interact, particularly in the PFC (Pisani et al, 2001;Alagarsamy et al, 2002Alagarsamy et al, , 2005Benquet et al, 2002;Homayoun and Moghaddam, 2006). Hence, mGluR5 is of current interest as a novel therapeutic target for the treatment of schizophrenia.…”