The Group III metabotropic glutamate receptors (mGluR) are located presynaptically on axon terminals and act as autoreceptors and heteroreceptors by inhibiting neurotransmitter release. Much has been learned about these receptors through exogenous application of L-serine-O-phosphate (L-SOP), an endogenous amino acid derivative and known activator of the Group III mGluRs. We hypothesized that L-SOP is the endogenous co-agonist at the high affinity Group III mGluR, mGluR4. We found the EC50 of L-SOP at mGluR4 was 0.5 μM, and determined that the concentration of L-SOP in whole brain was approximately 5 μM. An immunocytochemical survey revealed that cells containing the enzymatic machinery necessary for L-SOP synthesis and metabolism were observed in two brain regions known to express mGluR4, namely, cerebellum and hippocampus. In the cerebellum, the L-SOP synthetic and metabolic enzymes were found in Bergmann glia and Purkinje cells, two cells which form a tripartite synapse with parallel fiber axon terminals where the mGluR4 subtype is exclusively expressed at high levels. In the hippocampus, the L-SOP metabolic enzyme was detected in young neurons emanating from the neurogenic subventricular zone. Attempts to raise endogenous levels of L-SOP by crippling the L-SOP metabolizing enzyme (phosphoserine phosphatase), over-expressing the L-SOP synthesizing enzyme (phosphoserine aminotransferase), or through dietary protein restriction, to study the effects on neurotransmission and neurodevelopment in the central nervous system (CNS) were unsuccessful, suggesting that the production of L-SOP remains stable despite manipulation of the synthetic and metabolic enzymes. Finally, the ability of L-SOP to modulate glutamate release from presynaptic terminals was examined in cerebellar synaptosomes. Co-incident activation of presynaptic mGluR4 and presynaptic GABAA receptors facilitated glutamate release, suggesting that simultaneous activation of parallel fibers and Bergmann glia may serve to enhance synaptic transmission. This observation expands the traditional view of Group III mGluRs acting solely as inhibitory autoreceptors. Taken together, these results provide compelling evidence to support the hypothesis that L-SOP is the endogenous agonist at mGluR4, and possibly other Group III mGluRs.

The Group III metabotropic glutamate receptors (mGluR) are located presynaptically on axon terminals and act as autoreceptors and heteroreceptors by inhibiting neurotransmitter release. Much has been learned about these receptors through exogenous application of L-serine-O-phosphate (L-SOP), an endogenous amino acid derivative and known activator of the Group III mGluRs. We hypothesized that L-SOP is the endogenous co-agonist at the high affinity Group III mGluR, mGluR4. We found the EC50 of L-SOP at mGluR4 was 0.5 μM, and determined that the concentration of L-SOP in whole brain was approximately 5 μM. An immunocytochemical survey revealed that cells containing the enzymatic machinery necessary for L-SOP synthesis and metabolism were observed in two brain regions known to express mGluR4, namely, cerebellum and hippocampus. In the cerebellum, the L-SOP synthetic and metabolic enzymes were found in Bergmann glia and Purkinje cells, two cells which form a tripartite synapse with parallel fiber axon terminals where the mGluR4 subtype is exclusively expressed at high levels. In the hippocampus, the L-SOP metabolic enzyme was detected in young neurons emanating from the neurogenic subventricular zone. Attempts to raise endogenous levels of L-SOP by crippling the L-SOP metabolizing enzyme (phosphoserine phosphatase), over-expressing the L-SOP synthesizing enzyme (phosphoserine aminotransferase), or through dietary protein restriction, to study the effects on neurotransmission and neurodevelopment in the central nervous system (CNS) were unsuccessful, suggesting that the production of L-SOP remains stable despite manipulation of the synthetic and metabolic enzymes. Finally, the ability of L-SOP to modulate glutamate release from presynaptic terminals was examined in cerebellar synaptosomes. Co-incident activation of presynaptic mGluR4 and presynaptic GABAA receptors facilitated glutamate release, suggesting that simultaneous activation of parallel fibers and Bergmann glia may serve to enhance synaptic transmission. This observation expands the traditional view of Group III mGluRs acting solely as inhibitory autoreceptors. Taken together, these results provide compelling evidence to support the hypothesis that L-SOP is the endogenous agonist at mGluR4, and possibly other Group III mGluRs.