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Although N-Acetylaspartylglutamate (NAAG) was first reported in the mid 1960s to be present in the mammalian brain and spinal cord at mM concentrations, the critical experiments that established this peptide as a neurotransmitter emerged several decades later (reviewed in Neale et al., 2000). Since NAAG is by far the most prevalent and widely distributed peptide transmitter in the mammalian brain, it could be predicted to have roles in a broad spectrum of neuronal circuits and nervous system functions. A series of studies in animal models of clinical disorders have shown this to be the case (reviewed in Neale et al., 2005; 2011; Tsukamoto et al. 2007). A central element in defining the function of this peptide relates to its selective activation of the type 3 metabotropic “glutamate” receptor (mGluR3), a group II mGluR. This receptor has been localized to presynaptic terminals where it inhibits transmitter release via its negative coupling to cyclic nucleotides (reviewed in Niswender and Conn, 2010). As an endogenous mGluR3 agonist, NAAG has been shown to reduce cAMP and cGMP levels and to inhibit transmitter release (Adedoyin et al., 2010; Wroblewska et al., 1993; 1997; 1998, 2006; Zhao et al., 2001; Zhong et al., 2006). A model of the synaptic function of NAAG has emerged from a substantial literature on this peptide over the past 20 years and from data on other peptide cotransmitter actions in the perisynaptic space (Figure 1). Figure 1 A model of the role of NAAG peptidase inhibition and its influence on NAAG and NAAG2 in the nervous system (From Neale et al., 2011) The significance of NAAG in nervous system function has been most effectively studied through the development of inhibitors of the extracellular enzymes that inactivate it (Tsukamoto et al. 2007; Zhou et al., 2005). These inhibitors elevate extracellular levels of NAAG and consistent with NAAG activation of mGluR3, they reduce the release of other transmitters (Slusher et al., 1999; Zhong et al., 2006; Adedoyin 2010). The application of these inhibitors in vivo revealed that elevating the synaptic level of this peptide has considerable therapeutic potential in clinical conditions ranging from stroke and traumatic brain injury to inflammatory pain and schizophrenia (reviewed in Neale et al., 2005; 2011). NAAG peptidase inhibitors also may inhibit the extracellular hydrolysis of NAAG’s newly discovered sister peptide N-acetylaspartylglutamylglutamate (NAAG2) if it is synaptically released (Lodder-Gadaczek et al., 2011). Importantly, in these preclinical studies, the heterotropic mGluR2/3 antagonist LY341495 blocks the efficacy of NAAG peptidase inhibition (Neale et al., 2005; 2011). |
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