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PubMed1978

Comparison of the mechanism of isoproterenol-stimulated glycogenolysis in skeletal muscle of normal and phosphorylase kinase-deficient mice (I strain).

Diaphragm extracts from mice with the phosphorylase kinase deficiency mutation (I strain) have only 3.7% of the phosphorylase kinase activity of muscle extracts of the control strain (C57BL). Nevertheless, previous studies have shown that isoproterenol-stimulated glycogenolysis in I strain diaphragm muscle at a rate 57% (average relative response at 10 isoproterenol concentrations) of that of C57BL (GROSS, S.R., MAYER, S.E. and LONGSHORE, M.A.: J. Pharmacol. Exp. Ther. 198: 523-538, 1976). The present studies were initiated to compare the mechanism of isoproterenol-stimulated glycogenolysis in I and C57BL diaphragms. Isoproterenol was found to stimulate phosphorylase b to a conversion with an EC50 of 8 nM in muscles from mice of either strain, and the maximum increase in phosphorylase alpha activity in I diaphragms was 23% of that in C57BL diaphragms. Moreover, the initial rate of increase in phosphorylase alpha activity in I diaphragms incubated with 40 nM isoproterenol was 24% of that in C57BL muscles. The isoproterenol-stimulated increases in cyclic AMP content in diaphragms of the two strains were the same. Incubation of I diaphragms with isoproterenol did not significantly increase the concentrations of AMP, IMP or inorganic phosphate, activators of phosphorylase beta activity, nor was there a decrease in ATP and glucose 6-phosphate content, allosteric inhibitors of phosphorylase beta activity. Thus, phosphorylase alpha formation is the principal, if not only, catalyst of isoproterenol-stimulated glycogenolysis in skeletal muscle of phosphorylase kinase-deficient mice, and no evidence was obtained indicating that allosteric regulation of phosphorylase beta activity is part of the mechanism.

Adenine Nucleotides↗

PubMed1975

Prereplicative enzymic changes in regenerating rat liver.

After partial hepatectomy in rats, the following changes in enzymic activities were observed in the remnant liver during the prereplicative period. In the initial period of the prereplicative process, soon after removal of part of the liver, ornithine decarboxylase [EC 4.1.1.17] and IMP dehydrogenase [EC 1.2.1.14] increase. Subsequently, for entry into the S period, thymidine kinase [EC 2.7.1.75] increases simultaneously with increase in the intracellular cyclic AMP level and decrease in its phosphodiesterase [EC 3.1.4.17].

Animals↗

PubMed1992

Action of tiazofurin and 8-Cl-cAMP in human colon and pancreatic cancer cells.

Tiazofurin and 8-Cl-cAMP are novel chemotherapeutic agents shown to be effective against various cancer cells in vitro and in vivo. They act through distinct mechanisms that might modulate the signal transduction pathway, which causes growth inhibition, differentiation and down-regulation of c-ras and c-myc oncogene expression. We examined the effects of tiazofurin and 8-Cl-cAMP on colony formation of HT-29 human colon cancer and BxPC-3 and PANC-1 human pancreatic cancer cell lines. The IC50 of 8-Cl-cAMP was 0.1 and 0.2 microM in the pancreatic and colon cancer cell lines, respectively, and tiazofurin yielded IC50s from 4 (PANC-1) to 18 microM (HT-29). Simultaneous incubation with 8-Cl-cAMP and tiazofurin had additive effects on the inhibition of colony formation in the three examined cell lines. These results indicate possible clinical usefulness of a combination of tiazofurin and 8-Cl-cAMP in the treatment of colon and pancreatic carcinomas.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1977

Reduction in beta-adrenergic response of cultured glioma cells following depletion of intracellular GTP.

1. When C6 glioma cells were incubated with mycophenolic acid, a potent and specific inhibitor of IMP:NAD oxidoreductase (EC 1.2.1.14) there was a marked depletion of the cellular content of GTP. The viability of the cells was unaffected. 2. The adenosine 3':5'-monophosphate (cyclic AMP) response of C6 glioma cells to the beta-adrenergic stimulant, (+/-)isoprenaline, was considerably reduced after treatment with mycophenolic acid. The diminished response to (+/-)isoprenaline was prevented by the inclusion of guanine in the culture medium along with mycophenolic acid. 3. The adenylate cyclase response to (+/-)isoprenaline of whole homogenates from C6 cells treated with mycophenolic acid was also depressed; the response was restored to normal by the addition of GTP. 4. The adenylate cyclase response to (+/-)isoprenaline of a membrane fraction prepared from homogenates of C6 cells was almost totally dependent on the presence of added GTP. Membrane fractions from control and mycophenolic-acid-treated C6 cells gave similar adenylate cyclase responses to (+/-)isoprenaline in the presence of GTP. 5. It is concluded that mycophenolic acid may depress the beta-adrenergic sensitivity of C6 cells by depleting the cellular content of GTP.

Adenosine Triphosphate↗

PubMed1977

The significance of cAMP induced alterations in the cellular structure of Phycomyces.

Effect of cyclic AMP (cAMP) on Phycomyces blakesleeanus was studied by growing sporangiospores on glucose-asparagine agar or liquid medium containing three different levels of cAMP (10, 20 and 40 micronM) in addition to the control (no cAMP added). The response of Phycomyces to the exogenous cAMP concentration in the medium is as follows: (1) the time required for germ tube emergence is reduced; (2) the diameter of the mycelium is increased (sometimes more than 10 times) and frequency of branching is also increased; (3) the cell wall of the mycelium is thickened (in some cases more than 5 times); (4) the glycogen in the cytoplasm is decreased as visualized in thin sections and also demonstrated in biochemical quantitation; and (5) the distribution of intercalated membranous particles (Imp) on plasma membrane is altered and this can be easily detected in freeze-fractured replica. Such a change in Imp is seen in the formation of small clusters of aggregated particles on the plasmic half (PF) and craters on the complementary exoplasmic half (EF) of the plasma membrane. Although the mechanism of cAMP action requires further exploration, it is possible that the addition of cAMP to the culture medium leads to degradation of glycogen and enhancement of chitin synthesis since the cell wall is largely composed of chitin. The alteration in Imp may be related to a change in the activity of chitin synthetase which is a plasma membrane-bound enzyme.

Cyclic AMP↗

PubMed1980

Adenylate cyclase in silkworm. Effects of adenosine 3'-phosphate and 2'-deoxyadenosine 3'-phosphate on the enzyme system in fat body.

Adenosine 3'-phosphate and 2'-deoxyadenosine 3'-phosphate inhibit silkworm fat body adenylate cyclase. The inhibition has a rapid onset, and is dependent on the concentration of Mn2+ or Mg2+. The concentrations of 2'-deoxy-3'-AMP required for 50% inhibition (Ki) are 13 microM with 2 mM Mn2+ and 32 microM with 10 mM Mg2+. These Ki values are 7-30 times lower than that for 2'-deoxyadenosine. Stimulation of adenylate cyclase by NaF renders the activity more sensitive to the nucleotide inhibition, reducing the Ki value to 4 microM in the presence of Mn2+. The inhibitory activity is specific for adenine 3'-nucleotide; Ki for 2'-AMP and 5'-AMP are ten times or more higher than that for 3'-AMP, and the other 3'-nucleotides including 8-bromo-3'-AMP, 3'-IMP and 3'-GMP have little or no inhibitory activity.

Adenosine Monophosphate↗

PubMed1987

Effect of testosterone on purine synthesis de novo in rat perineal muscle in vivo.

We examined in vivo the influence of testosterone on purine synthesis de novo, in the levator ani and gastrocnemius muscles of the rat. The hypoxanthine, adenine and guanine contents and the rate of incorporation of [14C]formate into these purine bases were determined in castrated adult and prepubertal rats (groups 1 and 2) both before and after orchiectomy and, in the second case, at different times after testosterone treatment. Substantially similar behavior was found in both groups, with some specific differences. The results showed an increase in the basal levels after castration (except for a dramatic decrease in adenine and a rise in the Gua/Ade molar ratio in prepubertal rats) and a return to basal levels after hormone administration, which was also accompanied by variations in the Gua/Ade molar ratio. The kinetics of purine nucleotide synthesis de novo in vivo and, specifically, of the overall reactions: IMP formation from PRib-PP, IMP----AMP and IMP----GMP, were followed by evaluating the incorporation curves of [14C]formate into hypoxanthine, adenine and guanine. Our results show that testosterone administration enhanced the incorporation rate and gave characteristic patterns: a diphasic cyclic oscillation of the Ade values in adult castrated rats, and single peaks having a specific shape in the other cases. The Gua/Ade labeling ratio was unchanged in castrated rats and increased in both groups during the first 5 days after testosterone treatment, after which values even fell below normal; in most cases, values overlapped the pattern of the Gua/Ade molar ratio. The specific profile of the curves indicated that testosterone initially accelerated the turnover of guanylic acid and in the second phase re-established the normal behavior and ratio of AMP and GMP formation. These results indicate that the 'inosinic branch point' was subject to regulation by testosterone. The profiles of the incorporation curves and of the Gua/Ade ratio were indicative of a primary and secondary response to hormone action.

Adenine↗

PubMed1978

Rate-limiting factors in urate synthesis and gluconeogenesis in avian liver.

1. Urate synthesis and other metabolic characteristics of isolated chicken hepatocytes were studied. 2. The distinction is made between immediate precursors of the purine ring (glycine, glutamine, aspartate, formyltetrahydrofolate, bicarbonate) and ultimate precursors from which the immediate precursors are formed in the liver. 3. In hepatocytes from well-fed chickens the rate of urate synthesis was not greatly increased by the addition of amino acids or NH(4)Cl, but in hepatocytes from 72h-starved chickens the rate was much increased when alanine or asparagine was added as the only substrate. Other amino acids, when added alone, did not affect the rate. The exceptional effect of alanine and asparagine is due to the ready formation of the immediate precursors. 4. Conditions are described under which glutamine, serine, glycine plus formate, ribose and glucose increased the rate of urate synthesis. 5. At 1mm-NH(4)Cl (a concentration not much higher than that of blood plasma) the rate of urate synthesis in the presence of lactate was increased, but higher concentrations inhibited urate synthesis in the presence of lactate or alanine; with alanine even 1mm-NH(4)Cl was inhibitory. 6. Glucose synthesis from lactate, alanine or dihydroxyacetone was also inhibited by 1mm-NH(4)Cl. 7. NH(4)Cl inhibition of urate and glucose synthesis was paralleled by an increased rate of glutamine synthesis. Thus in the presence of NH(4)Cl the gluconeogenic precursors are diverted from the pathway of gluconeogenesis to that of glutamate and glutamine synthesis. This implies that the synthesis of these amino acids is the primary process in the detoxication of ammonia in the avian liver. 8. Urate synthesis, like urea synthesis, can be looked on as a cyclic process with either phosphoribosyl pyrophosphate or ribose acting as the carrier on which the purine ring is assembled. 9. The energy requirements of urate synthesis depend on whether phosphoribosyl pyrophosphate is regenerated from IMP by pyrophosphorylase or by phosphorylation and pyrophosphorylation of ribose. It is 6 or 9 pyrophosphate bonds of ATP respectively.

Acetates↗

PubMed1997

Tritrichomonas foetus: a strategy for structure-based inhibitor design of a protozoan inosine-5'-monophosphate dehydrogenase.

Inosine-5'-monophosphate dehydrogenase (IMPDH) is an attractive drug target for the control of parasitic infections. The enzyme catalyzes the NAD-dependent oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP), the committed step in guanosine monophosphate (GMP) biosynthesis. We have determined the crystal structures of IMPDH from the protozoan parasite Tritrichomonas foetus in the apo form at 2.3 A resolution and the enzyme-XMP complex at 2.6 A resolution. The enzyme forms a cyclic (C4) homotetramer. The core domain of each monomer forms an eight-stranded parallel beta/alpha barrel with the enzyme active site at the C-termini of the barrel beta strands which lies near the center of the fourfold axis of the tetramer. While the electron-density for XMP in the complex structure is well-defined, the NAD cofactor and a nearby loop containing the catalytic cysteine (Cys-319) are disordered. This disorder at the active site suggests that a high degree of flexibility may be inherent to the catalytic function of IMPDH, making this area a difficult target for structure-based inhibitor design. Unlike IMPDHs from other species, the T. foetus enzyme coordinates the substrate phosphate with a single arginine guanidinium in the active site. Furthermore, a deep groove extends 8 A from the substrate phosphate away from the sugar. This structural uniqueness forms the basis of our efforts to design compounds that specifically inhibit the parasite enzyme.

Animals↗

PubMed2002

Mechanism of retinoic acid induced attenuation of PTH action in UMR 106-01 cells.

Studies from our laboratory in osteoblast-like cells have shown that the increase in EGF receptor expression in response to PTH was cyclic AMP mediated and was blocked by treatment with retinoic acid (RA). The present studies investigate the mechanism for this effect of RA on PTH actions. UMR 106-01 cells were exposed to RA and were tested for cAMP response to PTH as well as for (125)I PTH binding. cAMP production in response to PTH was markedly decreased by RA (25.1 +/- 1.6% of control) whereas there was only a slight decrease in PTH binding in response to RA. For the study of adenylate cyclase activity, membranes were isolated from intact cells that had been exposed to RA. Treatment with RA decreased PTH-stimulated adenylate cyclase activity; however, forskolin-stimulated enzyme activity was unchanged. Treatment of intact cells with pertussis toxin, to inactivate Gi, did not alter the inhibitory effect of RA on PTH-stimulated adenylate cyclase activity. Addition of GppNHp, a non-hydrolyzable analogue of GTP, completely restored the response to PTH in the membranes. Therefore, we examined the activity of IMP dehydrogenase, the rate-limiting enzyme for GTP biosynthesis, and GMP reductase which counteracts the effect of the synthetic enzyme. Treatment with RA for 48 hours increased GMP reductase activity by 240.9 +/- 24.2% and decreased IMP dehydrogenase activity to 67.5 +/- 8.8% of control values. These data indicate that RA impairs the response to PTH in intact cells. This blunted response was preserved in membrane preparations but was corrected by GTP. The RA-induced alterations of enzymes involved in the GTP biosynthetic pathway in a direction that favors a decrease in GTP biosynthesis provide an explanation for the inhibitory effect of RA on PTH actions.

Adenylyl Cyclases↗

PubMed1985

Regulation of purine biosynthesis in G1 phase-arrested mammalian cells.

The effects of G1 phase growth arrest on purine biosynthesis were studied in cultured S49 T lymphoma cells. Incubations of wildtype S49 cells for 18 hr with dibutyryl cyclic AMP or forskolin, two agents which induced G1 arrest, reduced the rates of purine biosynthesis by 95%. Time course and concentration dependence studies indicated that the decrease in rates of purine biosynthesis correlated with the extent of G1 phase arrest. Similar studies with somatic cell mutants deficient in some component of cyclic AMP action or metabolism indicated that the depression in purine synthetic rates required G1 arrest and did not result from cell death. Rates of RNA and DNA synthesis were also markedly diminished in the growth arrested cells. Measurements of purine rates in the presence of azaserine indicated that the block in purine biosynthesis was prior to the formation of phosphoribosylformylglycinamide. Additionally, the activities of adenylosuccinate synthetase and IMP dehydrogenase were diminished in G1 arrested cells. The levels of all controlling enzymes, substrates, and cofactors, however, were not diminished in G1 arrested cells. Despite diminished rates of purine biosynthesis, the amounts of intracellular nucleotides in G1 cells were equivalent to those in exponentially growing cells. However, the concentrations of intracellular nucleotides were 30-50% higher in the growth arrested cells. These results suggested that perturbations in the consumption of nucleotides via inhibition of nucleic acid synthesis have profound effects on the purine pathway and indicated the importance of feedback inhibition by nucleotides in the regulation of purine synthesis in situ.

Animals↗

PubMed1984

Post-ischaemic synchronous purine nucleotide oscillations in perfused rat heart.

Langendorff perfused rat hearts show synchronous, statistically significant, systematic variations in ATP and ADP. Here we show that AMP and IMP also vary in register with ATP and ADP and we suggest that the synchronizing trigger for these oscillations may be ischaemia. Oscillations in the ATP/ADP ratio were found to be significantly correlated with creatine phosphate content but by contrast these quantities vary quite differently from the GTP/GDP ratio. Cyclic GMP oscillations showed a significant negative correlation with variations in ADP. Epinephrine raised mean cyclic AMP content and stabilized cyclic GMP oscillations, but had little other effect on the purine nucleotide variations.

Adenosine Diphosphate↗

PubMed1988

Regulation of skeletal muscle glycogenolysis during exercise.

Muscle-glycogen breakdown during exercise is influenced by both local and systemic factors. Contractions per se increase glycogenolysis via a calcium-induced, transient increase in the activity of phosphorylase a, and probably also via increased concentrations of Pi. In fast-twitch muscle, increases in the AMP and IMP levels may increase phosphorylase activity. The rate of muscle-glycogen breakdown during exercise depends on the pre-exercise glycogen concentration and is also influenced by hormones. Insulin may inhibit glycogen breakdown, whereas epinephrine enhances the rate of glycogen use in contracting muscle by increasing the phosphorylase a activity via increased cyclic AMP production. The availability of blood-borne substrates may also influence muscle glycogenolysis and, therefore, exercise performance.

Blood Glucose↗

PubMed2006

Combinatorial biosynthesis of novel antibiotics related to daptomycin.

Daptomycin, a cyclic lipopeptide produced by Streptomyces roseosporus, is the active ingredient of Cubicin (daptomycin-for-injection), a first-in-class antibiotic approved for treatment of skin and skin-structure infections caused by Gram-positive pathogens and bacteremia and endocarditis caused by Staphylococcus aureus, including methicillin-resistant strains. Genetic engineering of the nonribosomal peptide synthetase (NRPS) in the daptomycin biosynthetic pathway was exploited for the biosynthesis of novel active antibiotics. lambda-Red-mediated recombination was used to exchange single or multiple modules in the DptBC subunit of the NRPS to modify the daptomycin cyclic peptide core. We combined module exchanges, NRPS subunit exchanges, inactivation of the tailoring enzyme glutamic acid 3-methyltransferase, and natural variations of the lipid tail to generate a library of novel lipopeptides, some of which were as active as daptomycin against Gram-positive bacteria. One compound was more potent against an Escherichia coli imp mutant that has increased outer membrane permeability. This study established a robust combinatorial biosynthesis platform to produce novel peptide antibiotics in sufficient quantities for antimicrobial screening and drug development.

Amino Acid Sequence↗

PubMed1982

[Efficacy of PGF2 alpha on milk ejection during the sexual cycle of the cow].

After 30 days of lactation, 15 non-pregnant French Friesian cows were divided into groups A and B, balanced by the milk yield and lactation number of the cows. The 7 cows of group A were given a series of intrajugular prostaglandin F2 alpha (Upjohn Dinolytic) injections every morning, administered in increasing logarithmic doses (1, 4, 16, 64, 256, 1 024 micrograms). The aim of the experiment was to determine the minimal dose that would induce an increase in intramammary pressure (IMP) during the sexual cycle and milk let-down through a cannula in the teat cup. The 8 cows of group B were given a single injection of 256 micrograms of PGF2 alpha every morning to determine the changes during the sexual cycle in the response parameters of IMP (latency and amplitude) or of milk let-down (latency and collected volume) through a cannula. The following results were obtained: 1. The minimal dose of prostaglandin inducing milk let-down varied during the cycle; it was lower (1 to 16 micrograms) during the luteal phase (D4 to D12) than during the perioestral phase (256 to greater than 1 024 micrograms from D - 2 to D + 3) (figs. 2, 3). 2. During daily administration of the same dose (256 micrograms) of PGF2 alpha no response was obtained during the perioestral phase, while during the luteal phase; - maximal IMP deflection reached 12 to 14 mmHg (figs. 5, 6); - the volume of milk ejected was on an average higher than 3 liters per quarter (figs. 5, 6); - the latency time between injection and let down response was about 1.8 times shorter between D10 and D12 than between D4 and D5 (fig. 7). 3. The cyclic changes in the milk ejection parameters caused by PGF2 alpha were closely related to the plasma progesterone level (figs. 2, 3, 5, 6). The coefficients of correlation between the progesterone level and the - threshold dose: r = - 0.809** (group A), - volume of ejected milk: r = + 0.872*** (group B), - deflection amplitude: r = + 0.805*** (group B) were always significantly higher than the threshold of 0.001. Various hypotheses concerning the endocrine control of cyclic variations in milk let-down under the effect of PGF2 alpha are discussed.

Animals↗

PubMed2003

Antioxidant amplifies antibiotic protection in the cecal ligation and puncture model of microbial sepsis through interleukin-10 production.

Preadministration of antioxidants such as pyrrolidine dithiocarbamate (PDTC) and phenyl N-tert-butyl nitrone (PBN) protects animals from lethality in sepsis models. However, the requirement of preadministration greatly diminishes the clinical significance of these studies. Although the synthetic antioxidant PBN has been shown to effectively protect rodents from lethality in endotoxemia (lipopolysaccharide [LPS] model), preliminary screening indicates that pre- or postadministration of PBN does not protect in the rat cecal ligation and puncture (CLP) model. We show in this report that in a rat CLP model, the administration of PBN (150 mg/kg, 30 min after CLP) followed by the antibiotic imipenem (IMP; 10 mg/kg, 1 h after CLP) significantly increased survival compared with other single treatment groups. Previously, we have shown that PBN's protection in a rat LPS model is mediated by the overproduction of the anti-inflammatory cytokine interleukin (IL)-10. We show in this study that the increase in survival found in the PBN + IMP-treated group was abrogated by immunoneutralization with anti-IL-10 antibody, indicating that endogenous IL-10 is an effective protective factor. Plasma LPS levels were shown to be elevated after imipenem treatment, and the increased LPS level could have assisted to overproduce endogenous IL-10, as in the case of the PBN-treated LPS model. Statistical analysis indicated that the increase of IL-10 in PBN + IMP-treated group at early time period has significant association to the improvement of survival.

Animals↗

PubMed1975

[Role of adenine mono- and dinucleotides in ammonia formation in brain tissue].

The investigations carried out have shown that not only AMP but ADP also undergoes direct deamination in both soluble and mitochondrial fractions of rat brain tissue. Deamination of AMP is stimulated by the addition of ATP and the activity of one of the isoenzymes of AMP-aminohydrolase is markedly enhanced by both yeast and brain hexokinase. Activation by hexokinase is mainly due to its SH groups, through which hexokinase reacts with AMP-aminohydrolase, forming, probably, a protein-protein complex in which AMP aminohydrolase activity is considerably increased. Hexokinase does not affect the deamination of ADP and NAD. Further experiments are needed to find out whether the activation of AMP-aminohydrolase is accomplished by hexokinase itself or by an other protein contaminating it. Deamination of NAD, in contrast to AMP and ADP, takes place only in mitochondria and does not occur in the soluble fraction. In mitochondria besides deamination, AMP and ADP undergo intensive dephosphorylation, while the deamination of NAD is not accompanied by an increase of phosphate, i. e. mitochondria lack enzymes which breakdown NAD to mono nucleotides. Our data indicate that the formation of deamino -NAD from NAD and reamination of deamino-NAD by aspartate to NAD by the formation of intermediary NAD-succinate is of greater importance. The formation of the latter and that of deamino-NAD from NAD as well as the presence of preformed deamino-NAD in mitochondria have been demonstrated by Movsessian. The occurrence of these processes in mitochondria and their role in the formation of ammonia from amino acids is of importance in as much as oxaloacetate formation and its conversion to aspartate, which is necessary for the reamination of deamino-NAD, are localized in mitochondria. The main source of the amino nitrogen of aspartate is known to be glutamate, which incorporates the amino nitrogen of most amino acids. alpha-Keto-glutarate, which is necessary for the synthesis of glutamate, is also formed in mitochondria are the most favourable site for the formation of ammonia from amino acids with the participation of pyridine nucleotides. Of the purine mono and dinucleotides studied deamino-NAD is most effective in the formation of ammonia from amino acids in mitochondria since in contrast to purine mono nucleotides, deamino-NAD and NAD are not dephosphorylated in mitochondria. According to some authors the reamination of IMP by aspartate is of importance in the formation of ammonia from amino acids in brain tissue. In our studies, however, IMP was not effective in the formation of ammonia from aspartate in mitochondrial fractions. IDP was found to be more effective. IMP and IDP may probably participate in the formation of ammonia in the soluble fraction, where nucleotidase activity is considerably low.

AMP Deaminase↗

PubMed2000

Responses to umami substances in taste bud cells innervated by the chorda tympani and glossopharyngeal nerves.

The chorda tympani (CT) and glossopharyngeal (GL) nerves of several mammalian species respond differently to umami substances (US) such as monosodium glutamate (MSG), disodium 5'-inosinate (IMP) and disodium 5'-guanylate (GMP). In mice and rhesus monkeys, responses to US are greater in the GL than the CT nerve, with the GL nerve containing larger numbers of MSG-sensitive fibers. Gurmarin, a sweet response inhibitor, suppresses the mouse CT responses to the mixture of MSG and IMP to approximately 65% of control levels but not to the metabotropic and ionotropic glutamate agonists 2-amino-4-phophonobutyrate and N-methyl-D-aspartate. Gurmarin does not inhibit any taste responses in the GL. In mice, CT responses to MSG may be masked by their greater sensitivity to sodium ions. Calcium imaging studies demonstrate that some mouse taste cells isolated from the fungiform papilla innervated by the CT respond selectively (as indicated by a rise in intracellular Ca(2+) concentrations) to MSG and/or IMP or GMP. These MSG responses are not suppressed notably by reducing the Ca(2+) concentration of the stimulus solution, suggesting that the observed Ca(2+) release is from intracellular stores. Measurements of second messengers in the mouse fungiform papilla have revealed consistently that MSG elicits increases in both inositol 1,4,5-trisphosphate and adenosine 3', 5'-cyclic monophosphate levels. Together, these results suggest that US may stimulate two different transduction mechanisms in the fungiform papilla. They also suggest that gurmarin-insensitive components of receptors for US, including metabotropic and ionotropic glutamate receptors, may be commonly involved in transduction for umami taste in taste cells on both anterior and posterior parts of the tongue.

Animals↗