Neurochemistry Of Glycine
SYNTHESIS AND CATABOLISM OF GLYCINE
The details of glycine metabolism within neural tissue are poorly understood, and it is unclear to what extent neurons depend on de novo synthesis or uptake of glycine. Two enzymes are important in glycine metabolism; serine hydroxymethyltransferase (SHMT), which is thought to be present in the mitochondria of both neurons and glia, and the four-enzyme complex known as the glycine cleavage system (GCS), present in glia. SHMT catalyses the interconversion of L-serine and glycine while GCS catalyses the breakdown of glycine. Within neurons the action of SHMT leads to the conversion of L-serine to glycine, while in glia the coupling of SHMT and GCS results in the conversion of glycine to L-serine (Verleysdonk et al. 1999). The L-serine derived from glycine may be further metabolised, or released from glial cells to be taken up into neurons, forming a cycle analogous to the glutamine-glutamate cycle shown in Fig. 11.2. Glycine can also be formed by the action of aminotransferases (such as alanine-glyoxylate transaminase or glycine transaminase), in which the amino group from a donor amino acid is transferred onto glyoxlate, producing glycine and a keto acid.
STORAGE OF GLYCINE
Glycine, like GABA, is stored in synaptic vesicles. As described above, it seems likely that a common transport mechanism (VIAAT) is responsible for the accumulation of both amino acids. This lack of absolute specificity in the vesicular transporter means that the 'phenotype' of a neuron (GABAergic or glycinergic) is dictated by the relative concentrations of GABA and glycine in the cytosol. This will be determined by the expression of the respective biosynthetic enzymes and plasma membrane transporters. In certain cases neurons may release both GABA and glycine, which have been packaged into the same vesicles (Jonas, Bischofberger and Sandkuhler 1998; O'Brien and Berger 1999). The extent and significance of such co-release is unclear, but its effects will obviously depend on the types of pre- and postsynaptic receptors present at the synapse. Possible benefits of co-release may stem from the different kinetic properties of GABAA and glycine receptors, the ability to activate GABAB receptors or the modulatory action of glycine at NMDA receptors.
UPTAKE OF GLYCINE
Glycine is removed from the extracelluar space by high-affinity uptake into neurons and glia. Five glycine transporters have been identified in the CNS of mammals. All are members of the Na+- and Cl~-dependent family transporters and are encoded by two independently regulated genes, GLYT1 and GLYT2. Three GLYT1 isoforms (1a, b and c) and two GLYT2 isoforms (2a and b) are generated by alternative splicing (reviewed by
Figure 11.10 Glycine receptor pharmacology and structure, (a) Amino acids that act as agonists at glycine receptors, and strychnine a competitive antagonist. (b) Subunit composition of foetal and adult glycine receptors in the spinal cord. The receptors are shown with a pentameric assembly but the a and ft subunits are distinct from those that form GABAa receptors. Picrotoxin is also an effective glycine antagonist and in recombinant systems is selective for homomeric receptors foetal adult
Figure 11.10 Glycine receptor pharmacology and structure, (a) Amino acids that act as agonists at glycine receptors, and strychnine a competitive antagonist. (b) Subunit composition of foetal and adult glycine receptors in the spinal cord. The receptors are shown with a pentameric assembly but the a and ft subunits are distinct from those that form GABAa receptors. Picrotoxin is also an effective glycine antagonist and in recombinant systems is selective for homomeric receptors
Palacin et al. 1998). GLYT2 is found in neurons and GLYT1 is found predominantly in glia. The distribution of the transporters with respect to glycine receptors has led to the suggestion that both transporters are associated with glycinergic synapses, while GLYT1 may also regulate extracellular glycine levels at glutamatergic synapses and hence affect the activity of NMDA receptors. Relatively few selective blockers of glycine uptake have been described. GLYT1 isoforms are inhibited by sarcosine (N-methyl glycine) and various lipophillic derivatives of sarcosine, including NFPS (N[3-(4'-fluorophenyl)-3-(4'-phenyl-phenoxy)propyl]sarcosine) and ORG 24598 (Bergeron et al. 1998; Roux and Supplisson 2000). GLYT2a is inhibited by ORG 26176 but not by sarcosine.
Glycine receptors can be activated by a range of simple amino acids including glycine, ft-alanine and taurine, and are selectively blocked by the high-affinity competitive antagonist strychnine (Fig. 11.10). Glycine receptors were originally isolated from spinal cord membranes on the basis of strychnine binding, and found to be composed of two membrane-spanning polypeptides (termed a and ft) and an associated cytoplasmic protein (gephyrin). To date, four a subunit genes (a 1-4) and a single ft subunit gene have been identified, with several additional variants of the a1 and a2 isoforms produced by alternative splicing (reviewed by Kuhse, Betz and Kirsch 1995; Rajendra, Lynch and Schofield 1997). The a and ft subunits are formed from approximately 420 and 470 amino acids, respectively, are similar in structure to GABAa subunits, and likewise form pentameric receptors with a central ion channel permeable to Cl~ and HCO3. In recombinant expression systems the a subunits give rise to functional homomeric receptors or co-assemble to form heteromeric receptors. The ft subunit is only incorporated into receptors when co-expressed with a subunits. Native receptors in the adult spinal cord contain 3 al and 2 ß subunits whereas neonatal receptors are homomeric receptors formed from a2 subunits. The cytoplasmic protein gephyrin is not needed for the formation of functional receptors but plays an important role in the clustering of both glycine and GABAa receptors (Moss and Smart 2001).
Glycine receptors in the postsynaptic membrane, like GABAa receptors, most commonly generate a hyperpolarizing IPSP. In the brainstem, glycine receptors have also been shown to be present on presynaptic terminals, where they induce a small depolarisation that activates Ca2+ channels and increases neurotransmitter release (Turecek and Trussell 2001). This differs from the action of presynaptic GABAa receptors described above, where the depolarisation induced is sufficient to inactivate Na+ channels and decrease neurotransmitter release. Unlike GABAa receptors, glycine receptors are inhibited by some steroids, unaffected by benzodiazepines and are relatively insensitive to barbiturates. However, native and recombinant glycine receptors are positively modulated by a wide range of general anaesthetics, including diethyl ether, halothane, isoflurane, chloral hydrate, brometone and trichloroethylene.
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