Re:Re:Metabolism of amino acid neurotransmitters: the synaptic disorder underlying inherited metabolic diseases

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아미노산 신경전달물질과 항경련약물기전.pdf

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Fig. 1 Metabolic synopsis of the glutamatergic (excitatory) and GABAergic (inhibitory) synapse. 

The glutamate (Glu)/glutamine (Gln) (left) and GABA/glutamine (right) cycles as well as the dicarboxylic acid (DCA) shuttle between astrocytes and neurons (upper left) are described. This metabolic coupling between astrocytes and neurons is indispensable for recycling of glutamate and GABA and presynaptic availability of these neurotransmitters. Transamination reaction forming glutamate from 2-oxoglutarate (2-OG)—and vice versa—is strategically located including branched-chain aminotransferase (BCAT), alanine aminotransferase (ALAT), and aminoadipic semialdehyde (AAS) synthase (AASS). Disorders discussed in the text that interfere with these pathways and thus turn an inherited metabolic disease into a synaptic disorder are highlighted in red. For the sake of legibility, presynaptic effects of glutamate and GABA as well as metabolic pathways of L- and D-serine (D-Ser) and glycine (Gly) are not shown. 

Ala, alanine; BCKDHK-D, branchedchain ketoacid dehydrogenase kinase deficiency; CHCY, classical homocystinuria; EAAT, excitatory amino acid transporter; GAD, glutamate decarboxylase; GABAT, GABA transaminase; GAT2/3, GABA transporters 2 and 3; GE(-V), glycine encephalopathy (variants); GLDH, glutamate dehydrogenase; GLNT, glutamine transporter SLC38A2 (responsible for system A activity in most tissues); GLS, glutaminase; GS(-D), glutamine synthetase deficiency; ISO-D, isolated sulfite oxidase deficiency; KIC, ketoisocaproic acid; MoCo-D, molybdenum cofactor deficiency; MSUD, maple syrup urine disease; NaC2 and 3, sodium-dependent dicarboxylic acid transporters 2 and 3; OAD, organic acid disorders; OXPHOS-D, disorders of oxidative phosphorylation; PDE, pyridoxine-dependent epilepsy; PKU, phenylketonuria; Pyr, pyruvate; SN1, glutamine transporter SLC38A3 (system N activity); SSADH, succinic semialdehyde dehydrogenase; SDS, serine deficiency syndromes; TCA cycle, tricarboxylic acid cycle; UCD, urea cycle disorders

Abstract 

Amino acids are involved in various metabolic pathways and some of them also act as neurotransmitters. Since biosynthesis of L-glutamate and γ-aminobutyric acid (GABA) requires 2-oxoglutarate while 3-phosphoglycerate is the precursor of L-glycine and D-serine, evolutionary selection of these amino acid neurotransmitters might have been driven by their capacity to provide important information about the glycolytic pathway and Krebs cycle. Synthesis and recycling of amino acid neurotransmitters as well as composition and function of their receptors are often compromised in inherited metabolic diseases. For instance, increased plasma L-phenylalanine concentrations impair cerebral biosynthesis of protein and bioamines in phenylketonuria, while elevated cerebral L-phenylalanine directly acts via ionotropic glutamate receptors. In succinic semialdehyde dehydrogenase deficiency, the neurotransmitter GABA and neuromodulatory γhydroxybutyric acid are elevated. Chronic hyperGABAergic state results in progressive downregulation of GABAA and GABAB receptors and impaired mitophagy. In glycine encephalopathy, the neurological phenotype is precipitated by L-glycine acting both via cortical NMDA receptors and glycine receptors in spinal cord and brain stem neurons. Serine deficiency syndromes are biochemically characterized by decreased biosynthesis of L-serine, an important neurotrophic factor, and the neurotransmitters D-serine and L-glycine. Supplementation with L-serine and L-glycine has a positive effect on seizure frequency and spasticity, while neurocognitive development can only be improved if treatment starts in utero or immediately postnatally. With novel techniques, the study of synaptic dysfunction in inherited metabolic diseases has become an emerging research field. More and better therapies are needed for these difficult-to-treat diseases.

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Metabolism of amino acid neurotransmitters 

Rapid communication between neurons at chemical synapses is mediated by specific receptors which translate the chemical signal into changes of the postsynaptic membrane potential. Non-essential L-glutamate, the most abundant amino acid neurotransmitter, is the major excitatory neurotransmitter of the human central nervous system, particularly the cerebral cortex, hippocampus, amygdala, and basal ganglia. 2-Oxoglutarate, a Krebs cycle dicarboxylic intermediate, provides the carbon backbone for L-glutamate neosynthesis, followed by transamination using amino acids, particularly branched-chain amino acids (mediated by branched-chain amino acid transferase 1) and L-lysine (mediated by bi-functional aminoadipic semialdehyde synthase) as important amino group donors. However, since neurons are thought to lack pyruvate carboxylase and hence an important anaplerotic mechanism required to replenish Krebs cycle intermediates, they are metabolically handicapped regarding their ability to synthesize L-glutamate from glucose (Schousboe et al. 1997). Continuous loss of Lglutamate via vesicular release into the synaptic cleft, followed by new synthesis, would thus cause a constant drain of the Krebs cycle and, finally, severe bioenergetic impairment of neurons. To compensate for this loss, neurons and astrocytes collaborate using two metabolic shuttles known as dicarboxylic acid shuttle (Westergaard et al. 1994), providing neurons with dicarboxylic Krebs cycle intermediates, and glutamate/glutamine cycle (Schousboe et al. 1993) (Fig. 1). The glutamate/glutamine cycle fulfills at least three major functions: (1) recycling of the energy-rich carbon backbone of Lglutamate, (2) ammonium transfer, and (3) inactivation of synaptic L-glutamate and hence neurotransmitter homeostasis (Bak et al. 2006). Major components of this shuttle are uptake of synaptic L-glutamate by astrocytic excitatory amino acid transporters EAAT2 (synonym, SLC1A2) and EAAT1 (synonym, SLC1A3), two powerful molecular pumps that maintain up to 104 -fold L-glutamate gradients and are driven by a sodium gradient established by Na+ /K+ -ATPases. Next, L-glutamate is transformed by astrocyte-specific ATP-dependent glutamine synthetase to L-glutamine which is transported to neurons via system N glutamine transporter SN1 (synonym, SNAT3, SLC38A3) and system A glutamine transporter GLNT (synonym, SLC38A2). Presynaptic formation of Lglutamate using phosphate-activated glutaminase and, finally, storage of restored L-glutamate in synaptic vesicles complete the cycle. Postsynaptic effects of L-glutamate are mediated via fast-acting ionotropic (AMPA, kainate, and NMDA receptors) and G protein-coupled metabotropic glutamate receptors which modulate pre- and postsynaptic functions (Bak et al. 2006). L-Glutamate is not only the major excitatory neurotransmitter but also an essential component of intermediary metabolism, building block of proteins, energy substrate, neurotoxin, and eventually, the immediate precursor of the major inhibitory neurotransmitter GABA, highlighting that L-glutamate homeostasis requires tight coupling of several cells and functional elements. GABA, which is produced from L-glutamate by pyridoxal 5′-phosphate-dependent glutamate decarboxylase, is found in the interneurons, substantia nigra, striatum, globus pallidus, hypothalamus, periaqueductal gray matter, and hippocampus. In analogy to L-glutamate, neuronal neosynthesis of GABA from glucose is also handicapped due to lack of pyruvate carboxylase activity. As for L-glutamate, GABA is recycled by the GABA/glutamine cycle which, in concert with the glutamate/glutamine cycle, builds the glutamate/GABAglutamine cycle (Bak et al. 2006): First, the synaptic action of GABA is discontinued by astrocytic uptake via GABA transporters. In astrocytes, GABA enters the GABA shunt, starting with the formation of succinic semialdehyde by GABA transaminase, followed by formation of succinate by succinic semialdehyde dehydrogenase (Bak et al. 2006). Succinate enters the Krebs cycle and, via further metabolic transformation with the cycle, is converted to 2-oxoglutarate which is used for biosynthesis of L-glutamate and L-glutamine. Astrocytic L-glutamine then is transported back to neurons as described above, and presynaptic GABA is restored following decarboxylation of L-glutamate. Postsynaptic inhibitory effects of GABA are mediated via fast-acting ionotropic GABAA receptors and G protein-coupled GABAB receptors, forming a functional counterpart to glutamate receptors. Noteworthy, the chloride flux through GABAA receptors is thought to be ontogenetically regulated (Yamada et al. 2004). During the fetal and early neonatal period, i.e., before AMPA receptors are expressed, reverse chloride flux through GABAA receptors mediates fast depolarization of the postsynaptic membrane which is required to overcome the voltagedependent magnesium block of ligand-operated NMDA receptors. Therefore, GABAA receptors act in concert with excitatory NMDA receptors during brain development while the functionally antagonistic triumvirate of AMPA, NMDA, and GABAA receptors is established postnatally with the expression‎ of AMPA receptors. L-Serine, in analogy to L-glutamate, is involved in multiple reactions, particularly in the central nervous system, including the biosynthesis of nucleotides, phospholipids, proteins, and the neurotransmitters L-glycine and D-serine. Nonessential L-serine is synthesized in three enzymatic steps from 3-phosphoglycerate, an intermediate of the glycolytic pathway (Furuya 2008). Oxidation of 3-phosphoglycerate by phosphoglycerate dehydrogenase is followed by reductive transamination by phosphoserine transaminase to yield 3- phosphoserine which then is hydrolyzed to L-serine by phosphoserine phosphatase. L-Glycine is formed from L-serine by serine hydroxymethyltransferase 1 and D-serine by serine racemase which is predominantly expressed in neurons. L-Glycine is decarboxylated by the mitochondrial glycine cleavage system, composed of the four proteins T, P, L, and H (Kikuchi et al. 2008). L-Glycine and D-serine both bind to the L-strychnine-insensitive L-glycine binding site of excitatory NMDA receptors, acting as mandatory co-agonists, while, in addition, L-glycine is the major inhibitory neurotransmitter of the ventral spinal cord and brain stem, mediating its effect via strychnine-sensitive glycine receptors. Since amino acids are commonly involved in various metabolic pathways, depletion or accumulation of these metabolites as seen in some metabolic diseases is likely to activate different pathomechanisms. Therefore, specific interactions with neurotransmission cannot always be distinguished from other mechanisms affecting the brain. In the following, four examples— phenylketonuria (glutamatergic signaling) and succinic semialdehyde dehydrogenase deficiency (GABAergic signaling) as well as glycine encephalopathy and serine deficiency syndromes (glycinergic and serinergic signaling)—are briefly discussed, demonstrating how inherited metabolic diseases can affect amino acid-mediated metabolism.

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