Novel Proline Transporter Inhibitor (LQFM215) Presents Antipsychotic Effect in Ketamine Model of Schizophrenia.

The glutamatergic hypothesis of schizophrenia suggests a correlation between NMDA receptor hypofunction and negative psychotic symptoms. It has been observed that the expression of the proline transporter (PROT) in the central nervous system (CNS) is associated with glutamatergic neurotransmission, as L-proline has the capacity to activate and modulate AMPA and NMDA receptors. In this study, we aimed to investigate whether inhibition of proline transporters could enhance glutamatergic neurotransmission and potentially exhibit antipsychotic effects in an experimental schizophrenia model. Using molecular dynamics analysis in silico, we validated an innovative PROT inhibitor, LQFM215. We quantified the cytotoxicity of LQFM215 in the Lund human mesencephalic cell line (LUHMES). Subsequently, we employed the ketamine-induced psychosis model to evaluate the antipsychotic potential of the inhibitor, employing behavioral tests including open-field, three-chamber interaction, and prepulse inhibition (PPI). Our results demonstrate that LQFM215, at pharmacologically active concentrations, exhibited negligible neurotoxicity when astrocytes were co-cultured with neurons. In the ketamine-induced psychosis model, LQFM215 effectively reduced hyperlocomotion and enhanced social interaction in a three-chamber social approach task across all administered doses. Moreover, the compound successfully prevented the ketamine-induced disruption of sensorimotor gating in the PPI test at all tested doses. Overall, these findings suggest that PROT inhibition could serve as a potential therapeutic target for managing symptoms of schizophrenia model.

Crystal violet structural analogues identified by in silico drug repositioning present anti-Trypanosoma cruzi activity through inhibition of proline transporter TcAAAP069.

BACKGROUND: Crystal violet (CV) was used for several years in blood banks to eliminate the parasite Trypanosoma cruzi in endemic areas in order to prevent transfusion-transmitted Chagas disease. One mechanism of action described for CV involves inhibition of proline uptake. In T. cruzi, proline is essential for host cell infection and intracellular differentiation among other processes, and can be obtained through the proline permease TcAAAP069. METHODOLOGY/PRINCIPAL FINDINGS: CV inhibited proline transporter TcAAAP069 and parasites overexpressing this permease were 47-fold more sensitive to this compound than control parasites. Using CV as reference molecule, loratadine, cyproheptadine, olanzapine and clofazimine were identified as structurally related compounds to CV (structural analogues) by in silico drug repurposing through a similarity-based virtual screening protocol. All these already-approved drugs for clinical use inhibited TcAAAP069 activity with different efficacies and also presented trypanocidal action in epimastigotes, trypomastigotes and amastigotes of the Y, CL Brener and Dm28c T. cruzi strains. Finally, a synergistic effect between benznidazole and the CV chemical analogues was evidenced by combination and dose-reduction indexes values in epimastigotes and trypomastigotes of the Y strain. CONCLUSIONS/SIGNIFICANCE: Loratadine, cyproheptadine and clofazimine inhibit TcAAAP069 proline transporter and also present trypanocidal effect against all T. cruzi life stages in strains from three different DTUs. These CV structural analogues could be a starting point to design therapeutic alternatives to treat Chagas disease by finding new indications for old drugs. This approach, called drug repurposing is a recommended strategy by the World Health Organization to treat neglected diseases, like Chagas disease, and combination therapy may improve the possibility of success of repositioned drugs.

Evaluation of proline analogs as trypanocidal agents through the inhibition of a Trypanosoma cruzi proline transporter.

BACKGROUND: Trypanosoma cruzi, the etiological agent of Chagas disease, uses proline as its main carbon source, essential for parasite growth and stage differentiation in epimastigotes and amastigotes. Since proline is involved in many essential biological processes in T. cruzi, its transport and metabolism are interesting drug targets. METHODS: Four synthetic proline analogues (ITP-1B/1C/1D/1G) were evaluated as inhibitors of proline transport mediated through the T. cruzi proline permease TcAAAP069. The trypanocidal activity of the compounds was also assessed. RESULTS: The compounds ITP-1B and ITP-1G inhibited proline transport mediated through TcAAAP069 permease in a dose-dependent manner. The analogues ITP-1B, -1D and -1G had trypanocidal effect on T. cruzi epimastigotes with IC50 values between 30 and 40µM. However, only ITP-1G trypanocidal activity was related with its inhibitory effect on TcAAAP069 proline transporter. Furthermore, this analogue strongly inhibited the parasite stage differentiation from epimastigote to metacyclic trypomastigote. Finally, compounds ITP-1B and ITP-1G were also able to inhibit the transport mediated by other permeases from the same amino acid permeases family, TcAAAP. CONCLUSIONS: It is possible to design synthetic amino acid analogues with trypanocidal activity. The compound ITP-1G is an interesting starting point for new trypanocidal drug design which is also an inhibitor of transport of amino acids and polyamines mediated by permeases from the TcAAAP family, such as proline transporter TcAAAP069 among others. GENERAL SIGNIFICANCE: The Trypanosoma cruzi amino acid transporter family TcAAAP constitutes a multiple and promising therapeutic target for the development of new treatments against Chagas disease.

Structure and Dynamics Study of LeuT Using the Markov State Model and Perturbation Response Scanning Reveals Distinct Ion Induced Conformational States.

The bacterial leucine transporter (LeuT), a close homologue of the eukaryote monoamine transporters (MATs), currently serves as a powerful template for computer simulations of MATs. Transport of the amino acid leucine through the membrane is made possible by the sodium electrochemical potential. Recent reports indicate that the substrate transport mechanism is based on structural changes such as hinge movements of key transmembrane domains. In order to further investigate the role of sodium ions in the uptake of leucine, here we present a Markov state model analysis of atomistic simulations of lipid embedded LeuT in different environments, generated by varying the presence of binding pocket sodium ions and substrate. Six metastable conformations are found, and structural differences between them along with transition probabilities are determined. We complete the analysis with the implementation of perturbation response scanning on our system, determining the most sensitive and influential regions of LeuT, in each environment. Our results show that the occupation of sites Na1 and Na2, along with the presence of the substrate, selectively influences the geometry of LeuT. In particular, the occupation of each site Na1/Na2 has strong effects (in terms of changes in influence and/or sensitivity, as compared to the case without ions) in specific regions of LeuT, and the effects are different for simultaneous occupation. Our results strengthen the rationale and provide a conformational mechanism for a putative transport mechanism in which Na2 is necessary, but may not be sufficient, to initiate and stabilize extracellular substrate access to the binding pocket.

Trypanosoma cruzi Proline Transport Presents a Cell Density-dependent Regulation.

Trypanosoma cruzi, the etiological agent of Chagas disease, uses proline as its main carbon source, essential for parasite growth and stage differentiation in epimastigotes and amastigotes. Since proline is mainly obtained from extracellular medium by transport proteins, in this work we studied the regulation of the T. cruzi proline transporter TcAAAP069. Proline uptake and intracellular concentration presented oscillations during epimastigote growth phases, increasing during the early exponential phase (322 pmol/min) and decreasing to undetectable levels during the late exponential phase. Transporter expression rate correlated with proline uptake, and its subcellular localization alternated from both, the plasma membrane and close to the flagellar pocket, when the transport is higher, to only the flagellar pocket region, when the transport decreased until proline uptake and TcAAAP069 protein became undetectable at the end of the growth curve. Interestingly, when parasites were treated with conditioned medium or were concentrated to artificially increase the culture density, the proline transport was completely abolished resembling the effects observed in late exponential phase. These data highlight for the first time the existence of a density-associated regulation of relevant physiological processes such as proline metabolism.

SLC6A14 and 5-HTR2C polymorphisms are associated with food intake and nutritional status in children.

BACKGROUND: Serotonin plays a critical role in the regulation of food intake. The solute carrier family 6 member 14 (SLC6A14) and serotonin receptor 2C (5-HTR2C) genes are involved in the bioavailability and action of this neurotransmitter. OBJECTIVE: Evaluation of the association of six polymorphisms in these genes with food intake and nutritional status in children followed to 7-8years of age. DESIGN: Blood samples and the biodemographic data of 344 children were collected at three development stages, in a cross-sectional study undertaken with the cohort from a randomized trial. Polymorphisms were analyzed using polymerase chain reaction-based techniques. RESULTS: At 7 to 8years of age, carriers of the A alleles for both the SLC6A14 rs2312054 and SLC6A14 rs12391221 polymorphisms showed higher food intake, except for the sugar-dense food (SDF) intake parameter, than T/T and C/C homozygotes, respectively. Boy carriers of the C allele of rs2071877 had a higher sum of triceps and subscapular folds than T allele carriers at 7 to 8years old. For 5-HTR2C gene variants, A allele carriers (rs3813928) and T allele carriers (rs3813929) had higher food intake at 3 to 4years old than G/G and C/C homozygotes, respectively, except for SDF. At this age, the intake of energy-dense foods was higher in carriers of the T allele (rs3813929) than in C/C homozygotes. CONCLUSION: This study provides evidence that genetic variants of these proteins might be involved in the determination of food intake and nutritional status in children.

Feline cystinuria caused by a missense mutation in the SLC3A1 gene.

BACKGROUND: Cystinuria is an inherited metabolic disease that is relatively common in dogs, but rare in cats and is characterized by defective amino acid reabsorption, leading to cystine urolithiasis. OBJECTIVES: The aim of this study was to report on a mutation in a cystinuric cat. ANIMALS: A male domestic shorthair (DSH) cat with cystine calculi, 11 control cats from Wyoming, and 54 DSH and purebred control cats from elsewhere in the United States. METHODS: Exons of the SLC3A1 gene were sequenced from genomic DNA of the cystinuric cat and a healthy cat. Genetic screening for the discovered polymorphisms was conducted on all cats. RESULTS: A DSH cat showed stranguria beginning at 2 months of age, and cystine calculi were removed at 4 months of age. The cat was euthanized at 6 months of age because of neurological signs possibly related to arginine deficiency. Twenty-five SLC3A1 polymorphisms were observed in the sequenced cats when compared to the feline reference sequence. The cystinuric cat was homozygous for 5 exonic and 8 noncoding SLC3A1 polymorphisms, and 1 of them was a unique missense mutation (c.1342C>T). This mutation results in a deleterious amino acid substitution (p.Arg448Trp) of a highly conserved arginine residue in the rBAT protein encoded by the SLC3A1 gene. This mutation was found previously in cystinuric human patients, but was not seen in any other tested cats. CONCLUSIONS AND CLINICAL IMPORTANCE: This study is the first report of an SLC3A1 mutation causing cystinuria in a cat, and could be used to characterize other cystinuric cats at the molecular level.

Proline modulates the Trypanosoma cruzi resistance to reactive oxygen species and drugs through a novel D, L-proline transporter.

Trypanosoma cruzi, the etiological agent of Chagas' disease, has a metabolism largely based on the consumption of glucose and proline. This amino acid is essential for host cells infection and intracellular differentiation. In this work we identified a proline transporter (TcAAAP069) by yeasts complementation assays and overexpression in Trypanosoma cruzi epimastigotes. TcAAAP069 is mono-specific for proline but presents an unusual feature; the lack of stereospecificity, because it is competitively inhibited by the D- enantiomer. Parasites overexpressing TcAAAP069 have an increased intracellular proline concentration, 2.6-fold higher than controls, as a consequence of a higher proline transport rate. Furthermore, augmented proline concentration correlates with an improved resistance to trypanocidal drugs and also to reactive oxygen species including hydrogen peroxide and nitric oxide, emulating natural physiological situations. The IC50s for nifurtimox, benznidazole, H2O2 and NO. were 125%, 68%, 44% and 112% higher than controls, respectively. Finally, proline metabolism generates a higher concentration (48%) of ATP in TcAAAP069 parasites. Since proline participates on essential energy pathways, stress and drug resistance responses, these results provide a novel target for the development of new drugs for the treatments for Chagas' disease.

Mapping genetic variants underlying differences in the central nitrogen metabolism in fermenter yeasts.

Different populations within a species represent a rich reservoir of allelic variants, corresponding to an evolutionary signature of withstood environmental constraints. Saccharomyces cerevisiae strains are widely utilised in the fermentation of different kinds of alcoholic beverages, such as, wine and sake, each of them derived from must with distinct nutrient composition. Importantly, adequate nitrogen levels in the medium are essential for the fermentation process, however, a comprehensive understanding of the genetic variants determining variation in nitrogen consumption is lacking. Here, we assessed the genetic factors underlying variation in nitrogen consumption in a segregating population derived from a cross between two main fermenter yeasts, a Wine/European and a Sake isolate. By linkage analysis we identified 18 main effect QTLs for ammonium and amino acids sources. Interestingly, majority of QTLs were involved in more than a single trait, grouped based on amino acid structure and indicating high levels of pleiotropy across nitrogen sources, in agreement with the observed patterns of phenotypic co-variation. Accordingly, we performed reciprocal hemizygosity analysis validating an effect for three genes, GLT1, ASI1 and AGP1. Furthermore, we detected a widespread pleiotropic effect on these genes, with AGP1 affecting seven amino acids and nine in the case of GLT1 and ASI1. Based on sequence and comparative analysis, candidate causative mutations within these genes were also predicted. Altogether, the identification of these variants demonstrate how Sake and Wine/European genetic backgrounds differentially consume nitrogen sources, in part explaining independently evolved preferences for nitrogen assimilation and representing a niche of genetic diversity for the implementation of practical approaches towards more efficient strains for nitrogen metabolism.

SLC3A1 and SLC7A9 mutations in autosomal recessive or dominant canine cystinuria: a new classification system.

BACKGROUND: Cystinuria, one of the first recognized inborn errors of metabolism, has been reported in many dog breeds. HYPOTHESIS/OBJECTIVES: To determine urinary cystine concentrations, inheritance, and mutations in the SLC3A1 and SLC7A9 genes associated with cystinuria in 3 breeds. ANIMALS: Mixed and purebred Labrador Retrievers (n = 6), Australian Cattle Dogs (6), Miniature Pinschers (4), and 1 mixed breed dog with cystine urolithiasis, relatives and control dogs. METHODS: Urinary cystinuria and aminoaciduria was assessed and exons of the SLC3A1 and SLC7A9 genes were sequenced from genomic DNA. RESULTS: In each breed, male and female dogs, independent of neuter status, were found to form calculi. A frameshift mutation in SLC3A1 (c.350delG) resulting in a premature stop codon was identified in autosomal-recessive (AR) cystinuria in Labrador Retrievers and mixed breed dogs. A 6 bp deletion (c.1095_1100del) removing 2 threonines in SLC3A1 was found in autosomal-dominant (AD) cystinuria with a more severe phenotype in homozygous than in heterozygous Australian Cattle Dogs. A missense mutation in SLC7A9 (c.964G>A) was discovered in AD cystinuria in Miniature Pinschers with only heterozygous affected dogs observed to date. Breed-specific DNA tests were developed, but the prevalence of each mutation remains unknown. CONCLUSIONS AND CLINICAL IMPORTANCE: These studies describe the first AD inheritance and the first putative SLC7A9 mutation to cause cystinuria in dogs and expand our understanding of this phenotypically and genetically heterogeneous disease, leading to a new classification system for canine cystinuria and better therapeutic management and genetic control in these breeds.

Analysis of the CTNS gene in nephropathic cystinosis Mexican patients: report of four novel mutations and identification of a false positive 57-kb deletion genotype with LDM-2/exon 4 multiplex PCR assay.

OBJECTIVE: Identify CTNS gene mutations in nephropathic cystinosis Mexican patients. SUBJECTS AND METHODS: Eleven patients were included, nine presenting infantile nephropathic cystinosis and two siblings with the juvenile phenotype. The common 57-kb deletion was detected by multiplex PCR using large deletion marker-2 (LDM-2)/exon 4 set primers. Those alleles negative for 57-kb deletion were screened by single strand confirmation polymorphism (SSCP) and subsequent direct sequencing. RESULTS: In our sample, five mutations previously reported are identified: 57-kb deletion, EX4_EX5del, c.985_986insA, c.357_360delGACT, and c.537_557del. We detect a false assignation of 57-kb deletion homozygous genotype by using the LDM-2/exon 4 primers. In addition, four novel and severe mutations are identified: c.379delC, c.1090_1093delACCAinsCG, c.986C>G (p.T216R), and c.400+5G>A. CONCLUSIONS: Our sample of Mexican patients display allelic heterogeneity as compared to European or North American cystinosis cases. The identification of novel mutations might suggest the presence of exclusive American CTNS alleles in Mexican population. In order to prevent the false positive assignation of 57-kb deletion genotype, as caused by the presence of another type of intragenic CTNS gross deletion, we propose to analyze a different control CTNS exon to those originally reported in both LDM multiplex PCR assays, especially when parental DNA samples are not available.

Specific cognitive deficits in young children with cystinosis: evidence for an early effect of the cystinosin gene on neural function.

OBJECTIVES: Infantile nephropathic cystinosis is associated with a specific cognitive deficit in visual spatial processing in older children and adults. The cause of this deficit is unknown. This study was designed to determine whether the cognitive deficit is present in young children with cystinosis, suggesting an early effect of the genetic disorder on brain development. STUDY DESIGN: Young children (n = 25; age, 3-8 years) with cystinosis and 25 matched control subjects underwent cognitive testing, including tests of intelligence, visual perceptual, visual spatial, and visual motor functions. RESULTS: Children with cystinosis performed significantly more poorly on tests of visual spatial and visual motor function than did control subjects. Visual perceptual abilities were equivalent in the 2 groups. CONCLUSION: The same pattern of visual spatial deficit is present in young children with cystinosis as has previously been demonstrated in older children and adults, which suggests that there may be an influence of the cystinosis gene on brain development, rather than an adverse effect of prolonged cystine accumulation in the brain during childhood.

Phenotypic variability of a distinct deletion in McLeod syndrome.

The X-linked McLeod neuroacanthocytosis syndrome strongly resembles Huntington's disease and has been reported in various countries world-wide. Herein, we report two Chilean brothers with predominant psychiatric features at disease onset including schizophrenia-like psychosis and obsessive compulsive disorder. Molecular genetic analysis revealed a small deletion in the XK gene (938-942delCTCTA), which has been already described in a North American patient of Anglo-Saxon descent and a Japanese family, presenting with seizures, muscle atrophy or chorea yet absence of psychiatric features. These findings argue against a founder effect and indicate a profound phenotypic variability associated with the 938-942delCTCTA deletion. Our report supports the inclusion of McLeod syndrome in the differential diagnosis of Huntington's disease as well as acute psychosis in male subjects.

Síndrome de McLeod: compromiso multisistémico asociado a neuroacantocitosis ligada al cromosoma X, en una familia chilena / McLeod syndrome: Multisystem involvement associated with neuroacanthocytosis linked to X chromosome. Report of two related cases

Neurological abnormalities associated with spiculated, "acanthocytic" red cells in blood have been described as neuroacanthocytosis. This is a heterogeneous group of conditions that can be clearly subdivided on the basis of recent genetic findings. The McLeod Syndrome, one of the core neuroacanthocytosis syndromes, is a rare X-linked disorder caused by mutations of the XK gene, an X-chromosomal gene of unknown function characterized by haemopoietic abnormalities and late-onset neurological and muscular defects. We report two Chilean brothers with the McLeod phenotype who showed important psychiatric features. The diagnosis may be elusive if the presence of acanthocytosis is not properly studied. We describe a method which allowed the diagnosis that unmasked acanthocytosis. Otherwise the condition could have remained undiagnosed as it had been for decades in this family. This syndrome must be considered when assessing a familial movement disorder, specially affecting males with relevant psychiatric features. A reliable test for acanthocytosis assessment is available.

[McLeod syndrome: Multisystem involvement associated with neuroacanthocytosis linked to X chromosome. report of two related cases]. / Síndrome de McLeod: compromiso multisistémico asociado a neuroacantocitosis ligada al cromosoma X, en una familia chilena.

Neurological abnormalities associated with spiculated, "acanthocytic" red cells in blood have been described as neuroacanthocytosis. This is a heterogeneous group of conditions that can be clearly subdivided on the basis of recent genetic findings. The McLeod Syndrome, one of the core neuroacanthocytosis syndromes, is a rare X-linked disorder caused by mutations of the XK gene, an X-chromosomal gene of unknown function characterized by haemopoietic abnormalities and late-onset neurological and muscular defects. We report two Chilean brothers with the McLeod phenotype who showed important psychiatric features. The diagnosis may be elusive if the presence of acanthocytosis is not properly studied. We describe a method which allowed the diagnosis that unmasked acanthocytosis. Otherwise the condition could have remained undiagnosed as it had been for decades in this family. This syndrome must be considered when assessing a familial movement disorder, specially affecting males with relevant psychiatric features. A reliable test for acanthocytosis assessment is available.

A family with McLeod syndrome and calpainopathy with clinically overlapping diseases.

The authors describe a family with six patients with muscular dystrophy with a variable course. One is a compound heterozygote for CAPN3 mutations (calpainopathy) and the others have a single CAPN3 mutation. Linkage analysis and sequencing revealed a XK gene mutation (McLeod syndrome). This illustrates the variable phenotype of XK mutations and suggests the possibility that CAPN3 heterozygotes may have their condition caused by nonallelic mutations in other unrelated genes.

A McLeod phenotype detected by random screening for K:-4 [Kp(b-)] blood donors in Brazil.

BACKGROUND: The red blood cells of the McLeod phenotype have weak expression of Kell System antigens due to no expression of XK protein. STUDY DESIGN AND METHODS: One blood donor reacted as K:-4 [Kp(b-)] during a screening assay. Subsequent serologic studies demonstrated weak expression of K:4 and all other high-incidence Kell system antigens tested; however, no expression of Kx antigen was observed. RESULTS: One apparently healthy blood donor demonstrated low expression of K:2, K:4, K:5, K:7, K:14, K:22, and no Kx antigen in his red blood cells. His brother and mother showed the same weak expression, and his father showed normal expression of antigens tested. Flow cytometry studies confirmed the mother's status as a McLeod carrier female. Genotyping determined the presence of KEL2 and KEL4 alleles in mother and siblings. Southern blot with an exon-1 probe showed fragments shorter than predicted for the siblings and the mother, suggesting a deletion. Polymerase chain reaction with primers spanning exon 1 and flanking regions displayed a similar pattern. Deoxyribonucleic acid sequence allowed the precise characterization of a deletion of 392 bp, beginning at the 5' of the coding region up to nucleotide 201 of exon 1, which putatively abrogates the production of XK protein. CONCLUSION: Two brothers with McLeod phenotype in a Brazilian blood-donor population were identified. The molecular basis for this phenotype is a 392-bp deletion spanning from 5' of the coding region to exon 1 of the XK gene, never described before.

Nitric oxide synthesis requires activity of the cationic and neutral amino acid transport system y+L in human umbilical vein endothelium.

L-arginine transport is mediated by the cationic/neutral amino acid transport system y+L and cationic amino acid transporters y+/CATs in human umbilical vein endothelial cells (HUVECs). System y+/CATs activity may be rate-limiting for nitric oxide (NO) synthesis, but no reports have demonstrated system y+L involvement in NO synthesis in endothelium. We investigated the role of system y+L in NO synthesis in HUVECs. Transport of 1.5 microM L-arginine was inhibited (P < 0.05) by L-lysine (K(i), 1.4 micro M), L-leucine (K(i), 1.8 micro M) and L-phenylalanine (K(i), 4.1 microM), but was unaltered (P > 0.05) by L-alanine or L-cysteine. The system y+/CATs inhibitor, N-ethylmaleimide (NEM), did not alter 1.5 microM L-arginine transport, but inhibited (92 +/- 3 %) 100 microM L-arginine transport. L-arginine transport in the presence of NEM was saturable (V(max), 0.37 +/- 0.02 pmol (microg protein)(-1) min(-1); K(m), 1.5 +/- 0.3 microM) and competitively inhibited by L-leucine in the presence of Na+ (V(max), 0.49 +/- 0.06 pmol (microg protein)(-1) min(-1); K(m), 6.5 +/- 0.9 microM). HUVECs express SLC3A2/4F2hc, SLC7A7/4F2-lc2 and SLC7A6/4F2-lc3 genes encoding for the high-affinity transport system y+L. N(G)-Nitro-L-arginine methyl ester and L-leucine, but not NEM, inhibited NO synthesis in medium containing 1.5 microM L-arginine. Cells exposed to 25 mM D-glucose (24 h) exhibited reduced system y+L activity (V(max), 0.15 +/- 0.008 pmol (microg protein)(-1) min(-1); K(m), 1.4 +/- 0.3 microM) and NO synthesis. However, 25 mM D-glucose increased NO synthesis and L-arginine transport via system y+. Thus, L-arginine transport through system y+L plays a role in NO synthesis, which could be a determining factor in pathological conditions where the endothelial L-arginine-NO pathway is altered, such as in diabetes mellitus.

UGA4 gene expression in Saccharomyces cerevisiae depends on cell growth conditions.

In the yeast Saccharomyces cerevisiae, gamma-aminobutyric acid (GABA) transport is mediated by three permeases: the general amino acid permease GAP1, the proline permease PUT4 and the specific GABA permease UGA4. Expression of UGA4 gene is induced in the presence of GABA. We started a comparative study about UGA4 gene induction in cells grown on different culture media. Results presented here indicate that under certain growth conditions UGA4 permease is constitutive. Therefore, we demonstrate that in S. cerevisiae the UGA4 gene expression depends on cell growth conditions and that its synthesis not always depends on the presence of GABA.