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PubMed1998

Osmolarity-dependent glycine accumulation indicates a role for glycine as an organic osmolyte in early preimplantation mouse embryos.

Mouse zygotes and early cleavage-stage embryos are sensitive to increased osmolarity. However, development can occur at higher osmolarities if any of a number of organic compounds are present. One of the most effective of these is glycine. We have found that the amount of glycine accumulated by embryos during in vitro culture from the zygote to two-cell stage depends on the osmolarity of the medium, with significantly more glycine accumulated at 310 or 340 mOsM than at 250 mOsM. The accumulated glycine is largely retained in a freely diffusible form, as it can be released via a swelling-activated pathway in two-cell embryos. Increased glycine accumulation does not seem to depend on an increase in its rate of transport. The transport rate is not higher in two-cell embryos that have been cultured from zygotes in hypertonic vs. normal medium, and hypertonicity only slightly stimulates transport in zygotes. Our results indicate that glycine functions as an organic osmolyte in early mouse embryos.

Animals↗
PubMed1992

Glycine nitrogen in total parenteral nutrition: two prospective clinical trials comparing the efficacy of high and low glycine containing amino acid solutions.

Glycine has been regarded as a poor source of nitrogen for total parenteral nutrition. Two prospective randomised cross over controlled clinical trials were undertaken to compare the efficacy of high and low glycine containing amino acid solutions in parenterally fed malnourished hypoalbuminaemic patients with gastrointestinal disease. In the first study (n = 9), amino acid solutions in which glycine accounted for 23% and 4% of total nitrogen were compared. No statistically significant difference was found in urea nitrogen/total urinary nitrogen excretion (mean (SEM) 83.4 (1.4) v 81.6 (1.7)%, p = 0.31), nitrogen balance (-1.9 (2.4) v -0.6 (2.0) g/day, p = 0.31) or plasma protein concentrations and blood urea nitrogen. In the second extended study (n = 5), there was no significant difference in net whole body protein synthesis (+1.3 (4.7) v-0.2 (3.7) mg/kg/hour, p = 0.69) or fractional (0.403 (0.070) v 0.480 (0.41)%/hour, p = 0.68) and absolute albumin synthesis rates (6.0 (0.9) v 7.2 (0.06) mg/kg/hour, p = 0.22), on comparing solutions of 25% and 8% glycine nitrogen. In addition, a significantly higher proportion of total urinary nitrogen comprised urea when patients received the low glycine containing amino acid source (81.4 (2.5) v 83.8 (3.2)%, p = 0.04). It is concluded that there are no apparent short term nutritional or metabolic disadvantages to using amino acid solutions that contain up to 25% of nitrogen as glycine in total parenteral nutrition.

Adult↗
PubMed1979

Effects of glycine administration on canine experimental spinal spasticity and the levels of glycine, glutamate, and aspartate in the lumbar spinal cord.

Twelve female mongrel dogs were made paraplegic by midthoracic spinal cord transection. Beginning at 9 weeks posttransection, either glycine (50 mg/kg) or saline was injected intramuscularly each day and the signs of spinal spasticity were assessed clinically. After treating the dogs for 3 weeks, we removed the lumbar enlargement of each dog and microdissected it into gray and white areas which we assayed for glycine, glutamate, and aspartate content. Some of the clinical signs of spasticity improved in the animals injected with glycine compared to the saline-injected controls. The content of glycine was significantly elevated in the central gray matter and ventral medial white matter of the glycine-treated dogs. The levels of glutamate were also significantly elevated in the central, lateral ventral, and medial ventral gray matter and in the dorsal lateral and ventral medial white matter of the glycine-treated dogs. The possible role of these segmental putative neurotransmitters in spinal spasticity is discussed.

Animals↗
PubMed1989

Substitution of serine for alpha 1(I)-glycine 844 in a severe variant of osteogenesis imperfecta minimally destabilizes the triple helix of type I procollagen. The effects of glycine substitutions on thermal stability are either position of amino acid specific.

Recent reports have demonstrated that a series of probands with severe osteogenesis imperfecta had single base mutations in one of the two structural genes for type I procollagen that substituted amino acids with bulkier side chains for glycine residues and decreased the melting temperature of the triple helix. Here we demonstrate that the type I procollagen synthesized by cultured fibroblasts from a proband with a severe form of osteogenesis imperfecta consisted of normal molecules and molecules over-modified by post-translational reactions. The thermal stability of the intact type I collagen was normal as assayed by protease digestion under conditions in which a decrease in thermal stability was previously observed with eight other substitutions for glycine in the alpha 1(I) chain. In contrast, the thermal stability of the one-quarter length B fragment generated by digestion with vertebrate collagenase was decreased by 2-3 degrees C under the same conditions. Nucleotide sequencing of cDNAs and genomic DNA established that the proband had a substitution of A for G in one allele of the pro alpha 1(I) gene that converted the codon for alpha 1-glycine 844 to a codon for serine. The results also established that the alpha 1-serine 844 was the only mutation that could account for the decrease in thermal stability of the collagenase B fragment. There are at least two possible explanations for the failure of the alpha 1-serine 844 substitution to decrease the thermal stability of the collagen molecule whereas eight similar mutations decreased the melting temperature. One possibility is that the effects of glycine substitutions are position specific because not all glycine residues make equivalent contributions to cooperative blocks of the triple helix that unfold in the predenaturation range of temperatures. A second possible explanation is that substitutions of glycine by serine have much less effect on the stability of protein than the substitutions by arginine, cysteine, and aspartate previously studied.

Cell Line↗
PubMed1986

The glycine receptor deficiency of the mutant mouse spastic: evidence for normal glycine receptor structure and localization.

Homozygotes of the mutant mouse spastic exhibit reduced binding of 3H-strychnine to homogenates from various regions of the CNS compared with unaffected littermates (White and Heller, 1982). Here we report evidence that the spastic mutation coincides with a reduced concentration and an unaltered structure of the glycine receptor in spinal cord. Scatchard analysis of 3H-strychnine binding revealed a single binding site with a Bmax of 267 +/- 62 fmol/mg protein for spastic and of 864 +/- 220 fmol/mg protein for control mice; no difference was found for the corresponding KD values. Also Ki values of glycine for 3H-strychnine binding and displacement of 3H-strychnine by beta-alanine and taurine were indistinguishable for both preparations. Photoaffinity labeling of synaptic membranes with 3H-strychnine identified an Mr = 48,000 polypeptide in both control and spastic mouse membranes. Tryptic digestion of these membranes produced radiolabeled peptide fragments of identical molecular weights, suggesting that the proteolytic cleavage sites around the antagonist binding site are conserved in the mutant glycine receptor protein. Glycine receptors from both control and mutant mice were purified by affinity chromatography on aminostrychnine agarose. SDS/PAGE revealed three polypeptides of Mr = 48,000, 58,000, and 93,000 in both receptor preparations. Monoclonal antibodies directed against different subunits of the glycine receptor were applied to an enzyme-linked immunosorbent assay. The same pattern of immunoreactivity was obtained for glycine receptor from spinal cord of spastic homozygotes, control mice, and rats, suggesting conservation of the antigenic epitopes in the mutant receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Affinity Labels↗
PubMed2000

Glycine triggers an intracellular calcium influx in oligodendrocyte progenitor cells which is mediated by the activation of both the ionotropic glycine receptor and Na+-dependent transporters.

Using fluo-3 calcium imaging, we demonstrate that glycine induces an increase in intracellular calcium concentration ([Ca2+]i) in cortical oligodendrocyte progenitor (OP) cells. This effect results from a calcium entry through voltage-gated calcium channels (VGCC), as it is observed only in OP cells expressing such channels, and it is abolished either by removal of calcium from the extracellular medium or by application of an L-type VGCC blocker. Glycine-triggered Ca2+ influx in OP cells actually results from an initial depolarization that is the consequence of the activation of both the ionotropic glycine receptor (GlyR) and Na+-dependent transporters, most probably the glycine transporters 1 (GLYT1) and/or 2 (GLYT2) which are colocalized in these cells. Through this GlyR- and transporter-mediated effect on OP intrcellular calcium concentration [Ca2+]i, glycine released by neurons may, as well as other neurotransmitters, serve as a signal between neurons and OP during development.

Amino Acid Transport Systems, Neutral↗
PubMed1980

Purification and properties of glycine decarboxylase, a component of the glycine cleavage system, from rat liver mitochondria and immunochemical comparison of this enzyme from various sources.

Glycine decarboxylase, tentatively called P-protein as a constituent of the glycine cleavage system, was purified to near homogeneity from rat liver mitochondria. The purified P-protein was a homodimer with a molecular weight of about 210,000, consisting of identical subunits with a molecular weight of 105,000. In the exchange reaction of the carboxyl carbon of glycine wih CO2 catalyzed by the purified P-protein in the presence of H-protein, the pH optimum was 6.7, Km for glycine was 6.6 mM, and Km for H-protein was 7.4 microM. A specific rabbit antibody against the purified rat liver P-protein was prepared. Ouchterlony double diffusion analysis and immunoinhibition experiments using this antibody revealed immunological cross-reactivity among the P-proteins from various species of animals such as carp, frog, snake, chicken, bovine, and human, suggesting a quite conservative evolution of the glycine cleavage system.

Amino Acid Oxidoreductases↗
PubMed1981

Defective glycine cleavage system in nonketotic hyperglycinemia. Occurrence of a less active glycine decarboxylase and an abnormal aminomethyl carrier protein.

The activities of then glycine cleavage system in the liver and brain of patient with nonketotic hyperglycinemia was extremely low as compared with those of control human liver and brain. The activities of glycine decarboxylase (P-protein) and the aminomethyl carrier protein (H-protein), two of the four protein components of the glycine cleavage system, were considerably reduced in both the liver and brain; the extent of reduction was greater in the H-protein. The activity of the T-protein was normal. Purified H-protein from the patient did not react with lipoamide dehydrogenase, and titration of thiol groups with [2,3-14C]N-ethylmaleimide suggested that this H-protein is devoid of lipoic acid. This structural abnormality in the H-protein is considered to constitute the primary molecular lesion in this patient with non-ketotic hyperglycinemia. Immunochemical studies using an antibody specific for P-protein showed that the patient was due to reduction of the catalytic activity of the protein rather than a decrease in the actual amount of the P-protein. Partial inactivation of P-protein could result secondarily from impaired metabolism of glycine resulting from deficiency in the activity of H-protein. However, the H-protein from the patient could stimulate the P-protein catalyzed exchange of the carboxyl carbon of glycine with 14CO2, although the specific activity of the purified H-protein from the patient was only 4% of that of control human H-protein. The content of H-protein in the liver of the patient was approximately 35% of that of control human liver.

Amino Acid Metabolism, Inborn Errors↗
PubMed1989

Chemical modification of the glycine receptor with fluorescein isothiocyanate specifically affects the interaction of glycine with its binding site.

Fluorescein 5'-isothiocyanate (FITC) was used to modify lysine residues of the strychnine-sensitive glycine receptor. Pretreatment of rat spinal cord synaptic plasma membranes with FITC specifically affected the ability of glycine to displace [3H]strychnine binding. Glycine completely prevented the effect of FITC modification, suggesting the existence of lysine group(s) either at or in the vicinity of the agonist binding site. Labeling of purified glycine receptor with FITC indicates that such lysine residue(s) are located in the 48,000 daltons polypeptide. Chemical cleavage of the FITC-labeled 48-kilodalton subunit with N-chlorosuccinimide reveals two major labeled fragments of Mr 13.9 kilodalton and 8.5-kilodalton, respectively, the labeling of each being protected by glycine.

Animals↗
PubMed2003

Prepulse inhibition deficits of the startle reflex in neonatal ventral hippocampal-lesioned rats: reversal by glycine and a glycine transporter inhibitor.

BACKGROUND: Neonatal ventral hippocampal (NVH) lesions in rats induce behavioral abnormalities at adulthood thought to simulate some aspects of the positive, negative, and cognitive deficits classically observed in schizophrenic patients. Such lesions induce a postpubertal emergence of prepulse inhibition (PPI) deficits of the startle reflex reminiscent of the sensorimotor gating deficits observed in a majority of schizophrenic patients. To study the potential involvement of the glycinergic neurotransmission in such deficits, we investigated the capacity of glycine (an obligatory N-methyl-D-aspartate [NMDA] receptor co-agonist) and ORG 24598 (a selective glycine transporter 1 inhibitor) to reverse NVH lesion-induced PPI deficits in rats. METHODS: Ibotenic acid was injected bilaterally into the ventral hippocampus of 7-day-old pups. Prepulse inhibition of the startle reflex was measured at adulthood. RESULTS: Glycine (.8 and 1.6 g/kg IP) and ORG 24598 (10 mg/kg IP) fully and partially reversed lesion-induced PPI deficits, respectively. CONCLUSIONS: These findings confirm that an impaired glutamatergic neurotransmission may be responsible for PPI deficits exhibited by NVH-lesioned rats and support the hypoglutamatergic hypothesis of schizophrenia. They also suggest that drugs acting either directly at the NMDA receptor glycine site or indirectly on the glycine transporter 1 could offer promising targets for the development of novel therapies for schizophrenia.

Amino Acid Transport Systems, Neutral↗
PubMed2003

Inactivation of the glycine transporter 1 gene discloses vital role of glial glycine uptake in glycinergic inhibition.

The glycine transporter subtype 1 (GlyT1) is widely expressed in astroglial cells throughout the mammalian central nervous system and has been implicated in the regulation of N-methyl-D-aspartate (NMDA) receptor activity. Newborn mice deficient in GlyT1 are anatomically normal but show severe motor and respiratory deficits and die during the first postnatal day. In brainstem slices from GlyT1-deficient mice, in vitro respiratory activity is strikingly reduced but normalized by the glycine receptor (GlyR) antagonist strychnine. Conversely, glycine or the GlyT1 inhibitor sarcosine suppress respiratory activity in slices from wild-type mice. Thus, during early postnatal life, GlyT1 is essential for regulating glycine concentrations at inhibitory GlyRs, and GlyT1 deletion generates symptoms found in human glycine encephalopathy.

Amino Acid Transport Systems, Neutral↗
PubMed2005

Developmental regulation of beta-carboline-induced inhibition of glycine-evoked responses depends on glycine receptor beta subunit expression.

In this work, we show that beta-carbolines, which are known negative allosteric modulators of GABA(A) receptors, inhibit glycine-induced currents of embryonic mouse spinal cord and hippocampal neurons. In both cell types, beta-carboline-induced inhibition of glycine receptor (GlyR)-mediated responses decreases with time in culture. Single-channel recordings show that the major conductance levels of GlyR unitary currents shifts from high levels (> or = 50 pS) in 2 to 3 days in vitro (DIV) neurons to low levels (<50 pS) in 11 to 14 DIV neurons, assessing the replacement of functional homomeric GlyR by heteromeric GlyR. In cultured spinal cord neurons, the disappearance of beta-carboline inhibition of glycine responses and high conductance levels is almost complete in mature neurons, whereas a weaker decrease in beta-carboline-evoked glycine response inhibition and high conductance level proportion is observed in hippocampal neurons. To confirm the hypothesis that the decreased sensitivity of GlyR to beta-carbolines depends on beta subunit expression, Chinese hamster ovary cells were permanently transfected either with GlyR alpha2 subunit alone or in combination with GlyR beta subunit. Single-channel recordings revealed that the major conductance levels shifted from high levels (> or = 50 pS) in GlyR-alpha2-transfected cells to low levels (<50 pS) in GlyR-alpha2+beta-containing cells. Consistently, both picrotoxin- and beta-carboline-induced inhibition of glycine-gated currents were significantly decreased in GlyR-alpha2+beta-transfected cells compared with GlyR-alpha2-containing cells. In summary, we demonstrate that the incorporation of beta subunits in GlyRs confers resistance not only to picrotoxin but also to beta-carboline-induced inhibition. Furthermore, we also provide evidence that hippocampal neurons undergo in vitro a partial maturation process of their GlyR-mediated responses.

Animals↗
PubMed2000

Glycine receptor beta subunits play a critical role in potentiation of glycine responses by ICS-205,930.

The sensitivity of various types of recombinant glycine receptors (GlyRs) to ICS-205,930 was studied by fast perfusion in Xenopus laevis oocytes. This compound has previously been shown to potentiate glycine responses in rat spinal neurons between 10 nM and 1 microM, independently of its 5-HT(3) antagonist properties. In contrast, submicromolar concentrations of ICS-205,930 failed to affect responses of homomeric GlyRs formed from human alpha1 or alpha2 subunits, and micromolar concentrations (1-20 microM) acted differentially on the two types of homomeric receptors, potentiating the responses to glycine (10-20 microM) of alpha1 homomeric GlyRs and inhibiting the responses of alpha2 homomeric GlyRs. GlyRs beta subunits markedly influenced the modulations induced by ICS-205,930. In oocytes expressing alpha1/beta or alpha2/beta heteromeric GlyRs, low concentrations of ICS-205,930 (20 nM-1 microM) induced a potentiation of glycine responses that was counteracted by an inhibitory effect at higher concentrations. Thus, GlyRs beta subunits reduce by 2 orders of magnitude the concentration range potentiating alpha1-containing GlyRs and are required for potentiation of alpha2-containing GlyRs. These results reveal a new high-affinity potentiating site on GlyRs, to which beta subunits participate. The difference in ICS sensitivity between alpha1 and alpha2 GlyRs cannot be explained by their difference in TM2 segment and extracellular domains partly conserved between glycine and 5-HT(3) receptors are probably involved in the interaction of some 5-HT(3) antagonists with GlyRs.

Animals↗
PubMed2000

Functional consequences of reduction in NMDA receptor glycine affinity in mice carrying targeted point mutations in the glycine binding site.

We have used site-directed mutagenesis in conjunction with homologous recombination to generate two mouse lines carrying point mutations in the glycine binding site of the NMDAR1 subunit (Grin1). Glycine concentration-response curves from acutely dissociated hippocampal neurons revealed a 5- and 86-fold reduction in receptor glycine affinity in mice carrying Grin1(D481N) and Grin1(K483Q) mutations, respectively, whereas receptor glutamate affinity remained unaffected. Homozygous mutant Grin1(D481N) animals are viable and fertile and appear to develop normally. However, homozygous mutant Grin1(K483Q) animals are significantly lighter at birth, do not feed, and die within a few days. No gross abnormalities in CNS anatomy were detected in either Grin1(D481N) or Grin1(K483Q) mice. Interestingly, in situ hybridization and Western blot analysis revealed changes in the expression levels of NMDA receptor subunits in Grin1(D481N) mice relative to wild type that may represent a compensatory response to the reduction in receptor glycine affinity. Grin1(D481N) mice exhibited deficits in hippocampal theta burst-induced long-term potentiation (LTP) and spatial learning and also a reduction in sensitivity to NMDA-induced seizures relative to wild-type controls, consistent with a reduced activation of NMDA receptors. Mutant mice exhibited normal prepulse inhibition but showed increased startle reactivity. Preliminary analysis indicated that the mice exhibit a decreased natural aversion to an exposed environment. The lethal phenotype of Grin1(K483Q) animals confirms the critical role of NMDA receptor activation in neonatal survival. A milder reduction in receptor glycine affinity results in an impairment of LTP and spatial learning and alterations in anxiety-related behavior, providing further evidence for the role of NMDA receptor activation in these processes.

Animals↗
PubMed1991

The glycine cleavage system. Molecular cloning of the chicken and human glycine decarboxylase cDNAs and some characteristics involved in the deduced protein structures.

A cDNA encoding chicken glycine decarboxylase (pCP15b) was isolated using an antibody specific to this protein. Additional cDNAs were cloned with the aid of the genomic fragments obtained by using the pCP15b cDNA probe. No initiator methionine codon is found in the currently elucidated cDNA sequence, and an ATG codon in an exon is assigned to this role. The precursor glycine decarboxylase deduced from the 3514-base pair nucleotide sequence is comprised of 1,004 amino acids (Mr = 111,848). The 1,020 amino acid residues are encoded for the precursor form of human glycine decarboxylase (Mr = 112,869) in the 3,783-base long cDNA sequence of two 1.9-kilobase pair cDNAs with a pentanucleotide overlap. The pyridoxal phosphate binding site lysine and a glycine-rich region, which is suggested to be responsible for the attachment of the phosphate moiety of pyridoxal phosphate, are found in close proximity in both the chicken and human enzymes. This region essential for the enzyme action is suggested to be embedded in a segment rich in beta-turns and random coils and is surrounded by conserved and repetitive amino acid sequences. It is suggested that these structures are involved in the organization of the active site of glycine decarboxylase.

Amino Acid Oxidoreductases↗
PubMed1996

A microdialysis study of glycinamide, glycine and other amino acid neurotransmitters in rat frontal cortex and hippocampus after the administration of milacemide, a glycine pro-drug.

Milacemide is a glycinamide derivative which readily enters the brain and is metabolised to glycine. As its mechanism of action as an anticonvulsant drug is unknown we used the technique of microdialysis to study the temporal inter-relationship of glycinamide, glycine and other amino acid neurotransmitters in the extracellular fluid of rat hippocampus and frontal cortex. After milacemide administration (400 or 800 mg/kg i.p.), glycinamide concentrations rose linearly and dose-dependently in both hippocampus and frontal cortex. In contrast, whilst glycine concentrations rose in the hippocampus, glycine was unaffected in the frontal cortex. Concomitant increases in taurine hippocampal concentrations were observed. An increase in serine and a decrease in alanine concentrations was only observed at the highest milacemide dose (800 mg/kg). Other amino acids were affected. Thus, while glycinamide appears to be universally distributed throughout the brain, its metabolism to glycine and its effects on brain amino acids appear to be region specific.

Acetamides↗
PubMed1978

Glycine high affinity uptake and strychnine binding associated with glycine receptors in the frog central nervous system.

Accumulation of [3H]glycine into synaptosomal fractions occurs by high affinity systems in cerebral cortex, optic tectum, brain stem and spinal cord of the frog. Specific [3H]strychnine binding which appears associated with postsynaptic glycine receptors is also demonstrable in these regions. By contrast, only very low levels of strychnine binding and high affinity glycine uptake occur in higher centers of the rat central nervous system. The relative potencies of small neutral amino acids in competing for [3H]strychnine binding are similar in frog brain and spinal cord. No evidence for a high affinity accumulation of [3H]taurine by synaptosomal fractions of frog spinal cord can be demonstrated. These observations favor glycine rather than taurine as an inhibitory transmitter in frog spinal cord. Moreover, these findings suggest that glycine may have a synaptic role in higher brain centers in the frog.

Animals↗
PubMed1990

Glycine-related amino acids stereoselectively affect N-methyl-D-aspartate receptor-mediated contractions of guinea pig ileum: comparison with the inhibition of strychnine-insensitive [3H]glycine binding to rat cortical membranes.

Ten microM glycine, D-serine and D-alanine potentiated L-glutamate (30 microM)-induced contractions of the guinea pig ileum by an average of 35, 53 and 24%, respectively. On the contrary, D-cysteine, at the same concentration, caused a 21% inhibition of the contractile response to L-glutamate. This inhibitory effect of D-cysteine was abolished by 10 microM glycine. The corresponding L-isomers of these amino acids, namely L-serine, L-alanine and L-cysteine and the other amino acids tested, possessed negligible activity or were inactive in this test. The IC50 values of the same compounds for strychnine-insensitive binding of [3H]glycine (20 nM) to cortical membranes from the brain of the rat were: 0.26 microM, glycine; 1.2 microM, D-serine; 2.1 microM, D-alanine; 8.6 microM, D-cysteine; 51 microM, L-serine; 90 microM, L-alanine; greater than 1000 microM, L-cysteine. On the whole, these results point out a strict requirement for stereoselectivity for both of the effects examined. In addition, the results obtained in the ileum preparation suggest that D-cysteine may act as an antagonist, rather than as an agonist at the glycine site which regulates the responses of N-methyl-D-aspartate receptors.

Amino Acids↗