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PubMed1996

Proline is synthesized from glutamate during intragastric infusion but not during intravenous infusion in neonatal piglets.

Glutamate is considered the primary precursor amino acid for proline synthesis in mammals. Evidence exists, however, suggesting that proline may be a dietary indispensable amino acid for 2.5-kg piglets due to inadequate synthesis. This hypothesis was tested by intravenous and intragastric infusion of radiolabeled amino acids in vivo. Piglets (3 to 4 d old) were surgically implanted with catheters in the femoral (infusion) and jugular (sampling) veins and in the stomach (feeding and infusion). Piglets were fed hourly, via the stomach catheter, a semi-purified diet containing 10% dried skim milk, 15% corn oil, amino acids, vitamins and minerals. Experiment 1 was a 2 X 2 factorial design, with 24 piglets adapted to either low or supplemental proline diets (1.3 and 16.4 g proline x kg(-1) respectively) for 7 d, then intravenously infused with either [U-14C]glutamate or [U-14C]proline (185 k Bq x kg(-1) prime; 370 kBq x kg(-1) x h(-1) constant) for 4 h. Experiment 2 followed similar protocols, with eight piglets adapted to the low proline diet for 7 d and [U-14C]glutamate or [U-14C]proline infused into the stomach catheter. Piglets infused intravenously with [U-14C]glutamate did not convert glutamate to proline. Radioactive label was recovered in proline in all of the piglets receiving intragastric infusion of [U-14C]-glutamate. The fractional synthesis rate of proline from intragastric glutamate was 125 microgram ol kg(-1) x h(-1), accounting for approximately 40% of the proline accumulated. These data provide conclusive evidence that intravenously infused glutamate is not used as a precursor for proline synthesis and that, although conversion of glutamate to proline occurs in the gastrointestinal tract, the rate is not sufficient to provide the proline accumulated.

Animals↗
PubMed1987

Factors reducing and promoting the effectiveness of proline as an osmoprotectant in Escherichia coli K12.

Proline accumulation in Escherichia coli is mediated by three proline porters. Proline catabolism is effected by proline porter I (PPI) and proline/delta 1-pyrroline carboxylate dehydrogenase. Proline did not accumulate cytoplasmically when E. coli was subjected to osmotic stress in minimal salts medium. Although PPI is induced when proline is provided as carbon or nitrogen source, its activity decreased following growth of the bacteria in minimal salts medium of high osmotic strength. Proline dehydrogenase was induced by proline in low or high osmotic strength media. Proline porter II (PPII) was both activated and induced in osmotically stressed bacteria, though the dependencies of the two responses on medium osmolarity differed. Osmotic downshift during the transport measurement decreased the uptake of proline, serine and glutamine by bacteria cultured in media of high osmotic strength. Thus, while osmotic upshift caused specific activation of PPII, osmotic downshift caused a non-specific reduction in amino acid uptake. Glycine betaine inhibited the uptake of [14C]proline via PPII and PPIII but not via PPI. The dependence of that inhibition on glycine betaine concentration was similar when PPII was uninduced, induced or activated by osmotic stress, or induced by amino acid limited growth. Thus PPII and PPIII, not PPI, contribute to the mechanism of osmoprotection by proline and glycine betaine. The tendency for exogenous proline to accumulate in the cytoplasm of bacteria exposed to osmotic stress would, however, be countered by increased proline catabolism.

Amino Acids↗
PubMed1984

Proline transport and metabolism in Rickettsia prowazekii.

Purified Rickettsia prowazekii cells were able to transport L-proline. The influx of this amino acid had a Kt of 14 microM and a Vmax of about 64 pmol/min per mg of protein. Proline could not be transported by heat-killed or metabolically poisoned rickettsiae or at 0 degrees C. The uptake of proline was linear for almost 2 h. More than 90% of the accumulated intracellular radioactivity was proline. This intracellular pool could not be chased out of the cell by excess non-radioactive proline and did not exit into a proline-free medium. These results indicate that intracellular proline was bound or that the cell had a very limited efflux component for proline transport. The influx of proline was specific: among various analogs tested, only 3,4-dehydro-D,L-proline was effective in inhibiting proline uptake. R. prowazekii cells were unable to utilize proline as an energy source to drive hemolysis, and no measurable evolution from the rickettsiae of CO2 derived from proline occurred. The activities of the enzymes pyrroline-5-carboxylate-reductase and pyrroline-5-carboxylate dehydrogenase were not detectable. These enzymes are important in anabolism and catabolism of proline, respectively, and, if present in R. prowazekii have activities less than 1% of those in Escherichia coli.

1-Pyrroline-5-Carboxylate Dehydrogenase↗
PubMed1986

Protein synthesis in perfused rat lungs: determinations based on incorporation of radioactive proline.

Functional compartmentation and metabolism of radioactive proline was evaluated to define conditions under which synthesis of lung proteins could be measured accurately based on proline incorporation. Rat lungs were perfused with Krebs-Henseleit bicarbonate buffer equilibrated with O2/N2/CO2 (20:75:5) and containing 4.5% (w/v) bovine serum albumin, 5.6 mM glucose and amino acids at plasma levels. Intracellular proline increased linearly as perfusate proline concentration was increased from 108 microM, the plasma level, to 540 or 1080 microM. At each concentration, the pool of proline which provided precursors to protein synthesis rapidly reached a steady-state specific radioactivity, but when extracellular proline was 108 microM, this pool was diluted significantly by proline from endogenous sources. At 540 or 1080 microM extracellular proline, the specific radioactivities of perfusate and intracellular proline approached equality and rates of protein synthesis calculated based on the specific radioactivity of extracellular proline compared favorably with those calculated from the specific radioactivity of phenylalanyl-tRNA. Similar results were obtained in lungs of two groups of rats in which intracellular proline concentration differed 3-fold. Thus, the contribution of endogenous proline to the pathway of protein synthesis was minimized when extracellular proline was present at high concentration. Under this condition, calculations of protein synthesis based on proline incorporation were most accurate.

Animals↗
PubMed1990

Regulation of proline utilization in Salmonella typhimurium: how do cells avoid a futile cycle?

Salmonella typhimurium can degrade proline for use as a carbon, nitrogen, or energy source. To determine whether a futile cycle occurs which degrades the proline accumulated by proline biosynthesis, we studied the expression and enzymatic activity of the proline utilization (put) pathway under conditions which increase the concentration of the intracellular proline pools: catabolism of the dipeptide glycyl-proline, overproduction of proline due to a mutation which prevents feedback inhibition of proline biosynthesis, and accumulation of proline due to osmotic stress. The results indicate that: (i) internal proline induces the put genes, but only when accumulated to concentrations greater than the normal proline biosynthetic pool; and (ii) degradation of proline pools accumulated under high osmotic pressure is limited because proline oxidase is directly inhibited under these conditions.

Biological Transport↗
PubMed2005

Mitochondrial transport in proline catabolism in plants: the existence of two separate translocators in mitochondria isolated from durum wheat seedlings.

Abiotic stresses, such as high salinity or drought, can cause proline accumulation in plants. Such an accumulation involves proline transport into mitochondria where proline catabolism occurs. By using durum wheat seedlings as a plant model system, we investigated how proline enters isolated coupled mitochondria. The occurrence of two separate translocators for proline, namely a carrier solely for proline and a proline/glutamate antiporter, is shown in a functional study in which we found the following: (1) Mitochondria undergo passive swelling in isotonic proline solutions in a stereospecific manner. (2) Externally added L: -proline (Pro) generates a mitochondrial membrane potential (Delta Psi) with a rate depending on the transport of Pro across the mitochondrial inner membrane. (3) The dependence of the rate of generation of Delta Psi on increasing Pro concentrations exhibits hyperbolic kinetics. Proline transport is inhibited in a competitive manner by the non-penetrant thiol reagent mersalyl, but it is insensitive to the penetrant thiol reagent N-ethylmaleimide (NEM). (4) No accumulation of proline occurs inside the mitochondria as a result of the addition of proline externally, whereas the content of glutamate increases both in mitochondria and in the extramitochondrial phase. (5) Glutamate efflux from mitochondria occurs at a rate which depends on the mitochondrial transport, and it is inhibited in a non-competitive manner by NEM. The dependence of the rate of glutamate efflux on increasing proline concentration shows saturation kinetics. The physiological role of carrier-mediated transport in the regulation of proline catabolism, as well as the possible occurrence of a proline/glutamate shuttle in durum wheat seedlings mitochondria, are discussed.

Antiporters↗
PubMed1999

Influence of proline residues on the antibacterial and synergistic activities of alpha-helical peptides.

To investigate the influence of proline residues on the activity of alpha-helical peptides, variants were synthesized with insertions of proline residues to create peptides without proline, or with one or two prolines. The influence of the proline-induced bends was assessed by circular dichroism in the presence of liposomes, and the ability of the peptides to kill microorganisms, to permeabilize the outer and cytoplasmic membranes of Escherichia coli, to bind to liposomes, to form channels in planar lipid bilayers, and to synergize with conventional antibiotics. Representative peptides adopted alpha-helical conformations in phosphatidylcholine/phosphatidylglycerol (POPC/POPG, 7:3) liposomes as well as in 60% trifluoroethanol solution, as revealed by circular dichroism (CD) spectroscopy. However, the percent of helicity decreased as the number of proline residues increased. Tryptophan fluorescence spectroscopy showed that all of these peptides inserted into the membranes of liposomes as indicated by a blue shift in the emission maximum and an increase in the fluorescence intensity of the single tryptophan at residue 2. Quenching experiments further prove that the tryptophan residue was no longer accessible to the aqueous quencher KI. The peptide that lacked proline exhibited the highest activity [minimal inhibitory concentrations (MICs) of 0.5-4 microg/mL] against all tested Gram-negative and Gram-positive bacteria, but was hemolytic at 8 microg/mL. The single-proline peptides exhibited intermediate antibacterial activity. Peptides with two proline residues were even less active with moderate MICs only against E. coli. With only one exception from each group, the peptides were nonhemolytic. The ability of the peptides to demonstrate synergy in combination with conventional antibiotics increased as the antibacterial effectiveness decreased. All peptides bound to bacterial lipopolysaccharide and permeabilized the outer membrane of E. coli to similar extents. However, their ability to permeabilize the cytoplasmic membrane of E. coli as assessed by the unmasking of cytoplasmic beta-galactosidase decreased substantially as the number of proline residues increased. Correspondingly, increasing the number of proline residues caused a decreased ability to form channels in planar lipid bilayers, and the hemolytic, proline-free peptide tended to cause rapid breakage of planar membranes. Thus, the number of bends created by insertion of proline residues is an important determinant of antimicrobial, hemolytic, and synergistic activity.

Amino Acid Sequence↗
PubMed1987

Membrane association of proline dehydrogenase in Escherichia coli is redox dependent.

The PutA protein, product of the Escherichia coli gene putA, has two functions essential for proline utilization and for the regulation of putP and putA expression: as the peripheral membrane flavoprotein, proline dehydrogenase (EC 1.5.99.8), it transfers electrons from proline to the respiratory chain, and, as a repressor, it controls expression of genes putP and putA in response to proline supply. Association of proline dehydrogenase with the membrane was shown to require the simultaneous presence of the soluble enzyme, membranes, and proline. The kinetics of that association, monitored by following proline oxidation in a coupled enzyme assay system, were not altered when the transmembrane proton gradient generated during proline oxidation was dissipated by a proton ionophore. However, D-lactate or NADH could replace proline as a promoter of proline dehydrogenase-membrane association under anaerobic reaction conditions. These data imply that reduction of proline dehydrogenase and/or a membrane constituent promotes enzyme-membrane association. A biochemical mechanism is suggested whereby the concentration of proline dehydrogenase associated with the respiratory chain would be determined by proline supply.

Cell Membrane↗
PubMed2001

Depressor and bradycardic actions of L-proline injected into the nucleus tractus solitarii of anesthetized rats.

L-Glutamate has been considered to be a neurotransmitter in the nucleus tractus solitarius (NTS) of the afferent baroreflex pathway, though this has not yet been decisively shown. A bolus injection of a neurotransmitter candidate amino acid L-proline into the cisterna magna and that of L-glutamate shows the same pressor action in the freely moving rat, but the actual nuclei responding L-proline remain undetermined. Besides L-glutamate, L-proline might be another candidate amino acid in the NTS. The present study was therefore performed to characterize the circulatory action of L-proline injected into the NTS where responses to glutamate in the anesthetized rat had already been shown. The NTS was first determined as a site on the dorsal surface of the medulla where a microinjection of L-glutamate decreased arterial pressure and heart rate. Microinjected L-proline (1.65 to 13.2 nmol, 33 nl) into the NTS decreased arterial pressure and heart rate in a dose-dependent manner. The injection of a mixed solution (66 nl) of kynurenate, an ionotropic excitatory amino acid receptors antagonist (1.32 nmol), and L-proline (6.6 nmol) into the NTS abolished the depressor and bradycardic actions with L-proline alone (6.6 nmol, 66 nl). However, a mixture of an increased concentration of kynurenate (6.6 nmol) with glutamate augmented the actions seen with glutamate alone (0.66 nmol, 66 nl). D-Proline (13.2 nmol, 66 nl), the optic isomer of L-proline, produced no change in arterial pressure or heart rate, suggesting that the actions of L-proline in the NTS were optically specific. The results indicate that L-proline but not D-proline induces its depressor and bradycardic actions through ionotropic excitatory amino acid receptors in the NTS of the anesthetized rat. L-Proline may become a candidate transmitter of baroreceptor information in the NTS.

Anesthesia↗
PubMed1973

The effect of wilting on proline metabolism in excised bean leaves in the dark.

The effects of wilting on the fate of proline and on the rates of nonprotein proline formation and utilization have been determined in excised bean leaves. Wilting did not alter the fate of exogenously added (14)C-l-proline (2 mm) in either non-starved leaves (from plants previously in the light) or starved leaves (from plants previously in the dark). The fate of proline in nonstarved leaves was protein synthesis and in starved leaves was protein synthesis and oxidation to other compounds.Wilting caused an increase in non-protein proline formation, possibly including release by proteolysis and synthesis from precursors in both starved and nonstarved leaves. Wilting caused a decrease in proline utilization in nonstarved leaves by decreasing protein synthesis. In starved leaves, wilting caused an increase in the rate of proline utilization but this is due to the higher content of proline in wilted leaves compared to the turgid leaves which causes more proline utilization by oxidation. Thus, the primary effects of wilting which lead to the accumulation of proline were to decrease protein synthesis and to increase proline formation. The source of the proline is not known but the increased formation due to wilting is not affected by the carbohydrate content of the leaf. The role of carbohydrates is to prevent the loss of accumulating proline by oxidation.

Journal Article↗
PubMedDate not supplied

Proline trapping in granulomas, the site of collagen biosynthesis in murine schistosomiasis.

Proline, a critical substrate for collagen synthesis, is increased in liver undergoing fibrosis. In mice with schistosomiasis, the incorporation of proline into collagen occurs within liver granulomas. To study the interaction of liver cells and granulomas in the development of fibrosis, we assayed the enzymes that catalyze the formation and degradation of proline in isolated granulomas and liver. Two sequential enzymes involved in the formation of proline from arginine are ornithine-delta-aminotransferase and delta-pyrroline-5-carboxylate (P5C) reductase. Activities of both these enzymes in granulomas were approximately 10% of those in liver, expressed on the basis of DNA content. The enzymes involved in degradation of proline are proline oxidase and P5C dehydrogenase; both are present in liver cells. In isolated granulomas, activity of proline oxidase was minimal, and P5C dehydrogenase activity was absent. These findings suggest that the metabolism of proline within granulomas differs greatly from that in liver cells. Earlier studies showed that exogenous proline enters granulomas and is rapidly incorporated into collagen. The combined findings raise the possibility that granulomas serve as a proline trap. Proline can enter this compartment and can be incorporated into collagen; however, proline within granulomas cannot readily be diverted into other pathways by degradation.

Animals↗
PubMed2005

Proline metabolism in procyclic Trypanosoma brucei is down-regulated in the presence of glucose.

Proline metabolism has been studied in procyclic form Trypanosoma brucei. These parasites consume six times more proline from the medium when glucose is in limiting supply than when this carbohydrate is present as an abundant energy source. The sensitivity of procyclic T. brucei to oligomycin increases by three orders of magnitude when the parasites are obliged to catabolize proline in medium depleted in glucose. This indicates that oxidative phosphorylation is far more important to energy metabolism in this latter case than when glucose is available and the energy needs of the parasite can be fulfilled by substrate level phosphorylation alone. A gene encoding proline dehydrogenase, the first enzyme of the proline catabolic pathway, was cloned. RNA interference studies revealed the loss of this activity to be conditionally lethal. Proline dehydrogenase defective parasites grew as wild-type when glucose was available, but, unlike wild-type cells, they failed to proliferate using proline. In parasites grown in the presence of glucose, proline dehydrogenase activity was markedly lower than when glucose was absent from the medium. Proline uptake too was shown to be diminished when glucose was abundant in the growth medium. Wild-type cells were sensitive to 2-deoxy-D-glucose if grown using proline as the principal carbon source, but not in glucose-rich medium, indicating that this non-catabolizable glucose analogue might also stimulate repression of proline utilization. These results indicate that the ability of trypanosomes to use proline as an energy source can be regulated depending upon the availability of glucose.

Adenosine Triphosphate↗
PubMed2000

Neurotransmitter levels and synaptic strength at the Drosophila larval neuromuscular junction are not altered by mutation in the sluggish-A gene, which encodes proline oxidase and affects adult locomotion.

The sluggish-A (slgA) gene of Drosophila melanogaster has been shown to encode for the enzyme proline oxidase, a mitochondrial enzyme which catalyzes the first step in the conversion of L-proline to L-glutamate. The slgA transcript is expressed in both larval and adult Drosophila melanogaster. Mutations in this gene lead to reduced proline oxidase activity and an elevation of free proline levels. Adult mutant flies show a striking reduction of motor activity. Since proline oxidase may contribute to the supply of the neurotransmitter glutamate in the nervous system, a reduction in proline oxidase activity could reduce neural glutamate pools and affect synaptic transmission in neurons utilizing glutamate as a transmitter, including peripheral motor neurons. We tested the hypothesis that glutamate, and synaptic transmission mediated by glutamate, are reduced at synapses of glutamatergic motor neurons in slgA mutants. Levels of glutamate and proline in different cell compartments, and functional properties of synaptic transmission were compared in slgA and control specimens. Proline is elevated in muscle cells of slgA mutants, indicating that the slgA gene regulates tissue proline levels. In nerve terminal varicosities, proline levels were low in both mutants and controls. Glutamate levels in nerve terminal varicosities of slgA mutants and controls were similar. In addition, we found that glutamatergic synaptic transmission at individual nerve endings and at the whole-cell level was similar in slgA mutants and controls. Thus, proline oxidase does not play a major role in generating neuronal glutamate pools at the Drosophila larval neuromuscular junction, and larval neuromuscular performance is not altered significantly in slgA mutants. Metabolic pathways other than that involving proline oxidase are able to sustain glutamatergic synaptic function in Drosophila larvae.

Animals↗
PubMed2000

Importance of proline and other amino acids during honeybee flight--Apis mellifera carnica POLLMANN).

The levels of proline and other amino acids in the haemolymph and other body parts of honeybee foragers were investigated by HPLC analysis. The concentrations of proline in the blood of glucose-fed or -injected bees finishing their exhaustive tethered flights on a roundabout were significantly reduced compared to bees that were fed and rested for one hour. This indicates some utilization of proline during flight metabolism. The levels of essential amino acids and of the sum of all amino acids except proline remained roughly constant, indicating that the decrease of proline did not result from a changed haemolymph volume. 14C-labelled proline was injected into bees either shortly before starting their flight or before a resting period of equal duration in an incubator at the same temperature. Bees that rested had incorporated more proline into thorax body protein, and less of the labelled substance was unrecovered ("missing") and considered to be respired or less probably defecated. If the entire amount of missing 14C-proline is regarded as exhaled, the oxidative breakdown of proline reached higher levels after flight than in rested bees. This is another hint that proline is utilized during flight. Usually the exhaled amount did not exceed 10 microg proline in half an hour of flight. Although our data indicate involvement of proline in flight metabolism, the amount metabolized is low compared to the utilization of carbohydrates.

Animals↗
PubMed1986

Catalytic transfer of hydride ions from NADPH to oxygen by the interconversions of proline and delta 1-pyrroline-5-carboxylate.

Studies in reconstituted systems indicate that the interconversions of proline and delta 1-pyrroline-5-carboxylate can constitute a shuttle which transfers reducing equivalents into mitochondria as proline and oxidizing potential out as delta 1-pyrroline-5-carboxylate. The studies reported here determine if the transfer of reducing equivalents can be stoichiometrically greater than the utilization of shuttle intermediates. First, 3HOH production from [5-3H]proline was used to quantitate proline oxidation under conditions where delta 1-pyrroline-5-carboxylate could recycle back to proline in a system containing mitochondrial particles and pyrroline-5-carboxylate reductase. In parallel incubations the metabolic fate of [U-14C]proline was determined. 3HOH production continued to increase while no net change occurred in 14C-labeled proline and delta 1-pyrroline-5-carboxylate indicating catalytic activity in this system. In another system that contained intact mitochondria and pyrroline-5-carboxylate reductase, proline oxidation was quantitated by both [U-14C]proline recoveries and 3HOH production from [5-3H]proline. Proline oxidation was the same by both methods in incubations lacking NADPH and pyrroline-5-carboxylate reductase. However, it was significantly underestimated by [U-14C]proline recoveries as compared to 3HOH production in incubations containing all shuttle components. These results indicate catalytic functioning of the proposed shuttle in a reconstituted system containing intact mitochondria. This shuttle may function at specific times to catalytically generate cytosolic NADP+ and in turn regulate enzymes limited by [NADP+]. We suggest that the proposed shuttle may function to increase ribose-5-phosphate synthesis by the oxidative limb of the pentose phosphate pathway and inturn increase PP-ribose-P and purine synthesis during the initiation of cell growth.

Adenosine Triphosphate↗
PubMed1975

Effect of L-azetidine 2-carboxylic acid on growth and proline metabolism in Escherichia coli.

The effects of L-azetidine 2-carboxylic acid on growth and proline metabolism in a proline-requiring auxotroph of Escherichia coli are described. The homologue inhibited growth of the wild type and it, alone, did not substitute effectively for proline as a growth supplement for the mutant. In medium containing 0.05 mM proline, the addition of increasing amounts of homologue progressively inhibited growth of the wild type but stimulated growth of the mutant at homologue: proline ratios of 10 : 1 and 50 : 1. This suggested that the homologue exerted a "sparing effect" on proline in the mutant. The incorporation of L-[U-14C]proline and L-[3H]azetidine 2-carboxylic acid into hot trichloroacetic acid-insoluble material in the mutant was measured. Amino acid analysis of the insoluble material from cells incubated with radiolabeled proline alone revealed that proline was partially degraded and metabolized to other amino acids prior to incorporation into protein. The addition of unlabeled homologue to the incubation medium significantly reduced proline catabolism, suggesting that the homologue exerted a sparing effect on proline in this mutant. In medium containing unlabeled proline and radiolabeled L-azetidine 2-carboxylic acid, the homologue was incorporated both intact and partially degraded prior to incorporation into protein. Alanine was the major L-azetidine 2-carboxylic acid catabolite.

Amino Acids↗
PubMed1992

Molecular genetic analysis of proline and tryptophan biosynthesis in Streptomyces coelicolor A3(2): interaction between primary and secondary metabolism--a review.

We studied the control of proline metabolism and tryptophan biosynthesis in Streptomyces coelicolor A3(2), because proline is involved in secondary metabolism [undecylprodigiosin (Red) biosynthesis] whilst tryptophan, to our knowledge, is not. Proline transport was constitutive in wild-type cells, as were the enzymes of proline catabolism. When we analysed proline biosynthesis, we discovered that growth in the presence of proline stimulated rather than repressed the biosynthetic genes. We isolated proline transport mutants and to our surprise discovered that such strains overproduced Red. As well as losing the ability to transport proline, they had lost, to differing extents, the ability to degrade proline. However, proline biosynthesis appeared to be unaffected. It appears that proline anabolism and catabolism in S. coelicolor A3(2) is in a state of dynamic equilibrium and that if this balance is disturbed, Red biosynthesis can act as a sink for excess proline. We cloned the trpD and the trpCBA clusters of S. coelicolor A3(2) and identified a promoter within the latter cluster. This promoter appeared not to be regulated by the presence or absence of exogenous tryptophan, but rather by the growth phase and/or the growth rate of the culture. It appears, therefore, that an amino acid biosynthetic pathway that is apparently not involved in secondary metabolism in the streptomycete is regulated at the genetic level--not by feedback repression, but rather by the overall physiological state of the cell.

Proline↗
PubMed1997

Proline-induced potentiation of glutamate transmission.

The amino acid proline has long been suspected to serve as a modulator of synaptic transmission in the mammalian brain, but no such function has been identified. The selective expression of high affinity proline transport by a subset of glutamate pathways suggested that proline might play a role in synaptic transmission at these sites. This idea was tested with use of one such pathway, the Schaffer collateral-commissural projection to CA1 pyramidal cells of the rat hippocampus. Proline enhanced the initial slope of the field EPSP without affecting axonal excitability or the magnitude of paired-pulse facilitation. Proline-induced potentiation far outlasted the period of proline application and required the activation of NMDA receptors. Proline enhanced Schaffer collateral-commissural synaptic transmission even when the connections between areas CA1 and CA3 had been interrupted. Potentiation was observed with a proline concentration normally present in human CSF (3 microM). A concentration typical of CSF in persons with the genetic disorder hyperprolinemia type II (30 microM) produced a somewhat greater effect. Occlusion experiments suggested that proline-induced potentiation and tetanus-induced long-term potentiation utilize largely distinct transduction mechanisms. Proline-induced potentiation could be blocked by a prior high frequency stimulus, whether or not the stimulus evoked long-term potentiation. These results suggest that endogenous extracellular proline regulates the basal function of some glutamate synapses by maintaining them in a partially potentiated state. They may also facilitate understanding of the seizures and/or mental retardation associated with genetic disorders of proline metabolism.

2-Amino-5-phosphonovalerate↗