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PubMed2006

Factors affecting tyramine production in Enterococcus durans IPLA 655.

The decarboxylation of tyrosine by certain lactic acid bacteria leads to the undesirable presence of tyramine in fermented foods. Tyramine is the most frequent biogenic amine found in cheese and is also commonly found in other fermented foods and beverages. The tyramine-producing strain Enterococcus durans IPLA 655 was grown in a bioreactor under different conditions to determine the influence of carbon source, tyrosine and tyramine concentrations, and pH on tyramine production. The carbon source appeared to have no significant effect on the production of tyramine. In contrast, tyrosine was necessary for tyramine production, while the presence of tyramine itself in the growth medium inhibited such production. pH showed by far the greatest influence on tyramine synthesis; tyramine was produced in the greatest quantities at pH 5.0, although this was accompanied by a reduced growth rate.

Biogenic Amines↗
PubMed1982

The effects of amfonelic acid and some other central stimulants on mouse striatal tyramine, dopamine and homovanillic acid.

1 The concentrations of p- and m-tyramine, dopamine and homovanillic acid were measured in the mouse striatum following the subcutaneous administration of amfonelic acid, (+)-amphetamine or nomifensine.2 The administration of 2.5-25 mg/kg of amfonelic acid produced a reduction in p-tyramine that lasted at least 8 h. m-Tyramine was significantly increased and this was observed between 2 and 24 h after drug treatment. The levels of homovanillic acid were increased within 4 h after amfonelic acid administration.3 (+)-Amphetamine treatment (5 mg/kg) produced a reduction in p-tyramine observed up to 4 h after its administration and no significant changes in m-tyramine.4 The administration of 10 mg/kg of nomifensine produced no significant changes in p-tyramine, m-tyramine or homovanillic acid. By increasing the dose to 20 mg/kg, nomifensine produced an increase in p-tyramine and homovanillic acid.5 The present results support the view that amfonelic acid and (+)-amphetamine would respectively release granular or newly synthesized dopamine, both actions being accompanied by an increase in tyrosine hydroxylase activity and dopamine turnover which in turn reduces p-tyramine but produces no change or an increase in m-tyramine.6 The effects of nomifensine were observed after the administration of a relatively high dose (20 mg/kg), that was lethal to some mice (about 20%, at 2 h), and more likely to posses unspecific actions.

Amphetamine↗
PubMed1989

The influence of monoamine oxidase activity on the release of noradrenaline by tyramine.

The influence of monoamine oxidase (MAO) activity on the kinetic characteristics of noradrenaline (NA) release evoked by tyramine has been examined. Dog splenic artery strips were incubated with [3H]NA after inhibition of catechol-O-methyl-transferase (COMT) and of extraneuronal uptake. In some experiments MAO was also inhibited. The strips were then perifused for 200 min. Some strips were exposed to tyramine (1.5, 40 and 3240 mumols L-1) from the 100th to the 200th min of perifusion. In control experiments (i.e. in the absence of tyramine) most of the [3H]NA accumulated in the strips (83% of tissue activity) and did not contribute to the efflux. The value of this "bound fraction" (the NA located at a site(s) from which it could not be displaced by a simple concentration gradient) was the same whether or not MAO was inhibited. At all concentrations, tyramine mobilized only one NA compartment. Increasing the concentration of tyramine resulted in a decrease of the "bound fraction", which became negligible for the highest concentration of tyramine used (3240 mumols L-1), regardless of MAO being inhibited or not. However, for the lower concentrations of tyramine, MAO inhibition resulted in an increase in the amine's releasing effect. The formation of 3,4-dihydroxy-phenylglycol (DOPEG) increased with increase of tyramine from the 1.5 to 40 mumols L-1 concentration, but not beyond. The ratio NA/DOPEG increased for all concentrations of tyramine. Thus, it was not possible to exclude an inhibitory effect of tyramine on MAO activity with the highest concentration used.

Animals↗
PubMed1976

Regulation of tyramine oxidase synthesis in Klebsiella aerogenes.

Tyramine oxidase in Klebsiella aerogenes is highly specific for tyramine, dopamine, octopamine, and norepinephrine, and its synthesis is induced specifically by these compounds. The enzyme is present in a membrane-bound form. The Km value for tyramine is 9 X 10(-4) M. Tyramine oxidase synthesis was subjected to catabolite repression by glucose in the presence of ammonium salts. Addition of cyclic adenosine 3',5'-monophosphate (cAMP) overcame the catabolite repression. A mutant strain, K711, which can produce a high level of beta-galactosidase in the presence of glucose and ammonium chloride, can also synthesize tyramine oxidase and histidase in the presence of inducer in glucose ammonium medium. Catabolite repression of tyramine oxidase synthesis was relieved when the cells were grown under conditions of nitrogen limitation, whereas beta-galactosidase was strongly repressed under these conditions. A cAMP-requiring mutant, MK54, synthesized tyramine oxidase rapidly when tyramine was used as the sole source of nitrogen in the absence of cAMP. However, a glutamine synthetase-constitutive mutant, MK94, failed to synthesize tyramine oxidase in the presence of glucose and ammonium chloride, although it synthesized histidase rapidly under these conditions. These results suggest that catabolite repression of tyramine oxidase synthesis in K. aerogenes is regulated by the intracellular level of cAMP and an unknown cytoplasmic factor that acts independently of cAMP and is formed under conditions of nitrogen limitation.

Amino Acid Oxidoreductases↗
PubMed2003

Neurovascular dissociation with paradoxical forearm vasodilation during systemic tyramine administration.

BACKGROUND: Despite the widespread use of tyramine as a pharmacological tool to assess the effects of norepinephrine release from sympathetic nerve terminals, its vascular effects are not adequately characterized. In particular, previous results indicate that intravenous tyramine produces little if any systemic vasoconstriction, suggesting that tyramine does not cause significant norepinephrine release from sympathetic nerves innervating peripheral vascular beds. To test this hypothesis, we determined the effects of intravenous tyramine on local forearm norepinephrine spillover and vascular resistance. METHODS AND RESULTS: Seven healthy subjects were studied with systemic and local forearm norepinephrine spillover and forearm blood flow at baseline, during systemic tyramine infusion, and after sympathetic stimulation induced by the cold pressor test. Tyramine infusion caused a significant increase in systemic and forearm norepinephrine spillover. The amount of norepinephrine released into the forearm by tyramine was similar to that caused by cold pressor stimulation, 0.15+/-0.05 versus 0.18+/-0.05 ng x dL(-1) x min(-1). As expected, forearm vascular resistance increased during the cold pressor test, but tyramine produced forearm vasodilation (4.5+/-1 versus -5+/-1 mm Hg x dL(-1) x min(-1), P<0.03) despite the increase in local norepinephrine spillover. In 6 additional subjects, plasma dopamine increased significantly during tyramine administration, from 11+/-3 to 662+/-105 pg/mL. CONCLUSIONS: Thus, systemic tyramine infusion evokes a significant increase in peripheral norepinephrine spillover, and this, paradoxically, is associated with local vasodilatation rather than vasoconstriction.

Adult↗
PubMed2005

Tyramine-induced vasodilation mediated by dopamine contamination: a paradox resolved.

We reported previously that intravenous administration of tyramine induced a paradoxical forearm vasodilation and an increase in plasma dopamine, raising the possibility that dopamine is released by or converted from tyramine in vivo. Alternatively, tyramine can be nonenzymatically oxidized into dopamine in vitro, and this contamination may be responsible for the increase in plasma dopamine and forearm vasodilation. To distinguish between these possibilities, we measured the hemodynamic and neurohumoral effects of an intravenous infusion of a specially prepared dopamine-free tyramine solution in 8 normal volunteers at a dose that increased systolic blood pressure by approximately 25 mm Hg (from 107+/-5 to 133+/-5 mm Hg; P <0.001) and compared it with an equivalent dose of norepinephrine. Tyramine increased plasma norepinephrine (139+/-18 to 226+/-30 pg/mL; P <0.02), its intraneuronal metabolite dihydroxyphenylglycol (980+/-73 to 2245+/-206 pg/mL; P <0.001), and systemic vascular resistance, but not plasma dopamine or its intraneuronal metabolite dihydroxyphenylacetic acid. Tyramine and norepinephrine produced nonsignificant increases in forearm vascular resistance. We conclude that tyramine-induced forearm vasodilation reported in previous studies is explained by the presence of dopamine contamination in tyramine preparations. Intravenous administration of dopamine-free tyramine and norepinephrine produced equivalent systemic vasoconstriction. The forearm vasculature was not useful in monitoring the vasoconstrictive effects of either agent. The possibility of dopamine contamination needs to be considered when interpreting previously published studies using tyramine as a pharmacological tool to assess sympathetic function, and it must be avoided in future studies.

Adult↗
PubMed1988

On tyramine, food, beverages and the reversible MAO inhibitor moclobemide.

The pathways for the biosynthesis and metabolism of tyramine are described as a basis for the discussion of the interaction between MAO inhibitors and tyramine. While a role of endogenous tyramine in the antidepressant action of MAO inhibitors remains purely hypothetical at this time, the mechanisms leading to the potentiation of the tyramine pressor effect ("cheese effect") are well known. Experiments in animals and man have provided concordant quantitative information on the effect of irreversible and some novel reversible MAO inhibitors on the presystemic disposition of orally ingested tyramine and on the noradrenaline-releasing action of tyramine in noradrenergic nerve terminals. There is a profound difference in the magnitude of tyramine potentiation between the irreversible inhibitor tranylcypromine and the reversible inhibitor moclobemide. A systematic analysis of the tyramine content of current European food and beverage is reported and serves as a rational basis for providing advice to patients on moclobemide. Most of the food and beverages analyzed contain less tyramine than previously reported and a few rules concerning rare cheeses with high tyramine content are sufficient to eliminate the risk of hypertensive crises.

Animals↗
PubMed1998

Dopamine formation from tyramine by CYP2D6.

Dopamine is formed form L-tyrosine by tyrosine hydroxylase and aromatic L-amino acid decarboxylase. In addition to this pathway, however, the formation of catecholamines, including dopamine, from trace amines such as tyramine by hepatic microsomes has been demonstrated. In this study, we investigated the formation of dopamine from trace amines, using human hepatic microsomes and human cytochrome P450 (CYP) isoforms expressed in yeast. Among the 11 isoforms of human CYP expressed in yeast, CYP2D6 was the only isoform exhibiting strong ability to convert p-tyramine and m-tyramine to dopamine. In studies with human hepatic microsomes, the hydroxylation of tyramine to dopamine was inhibited by bufuralol, a typical substrate for CYP2D isoforms, and anti-CYP2D1 antiserum. This is the first report showing that CYP2D is capable of converting tyramine to dopamine. The Km values of CYP2D6, expressed in yeast, for p-tyramine and m-tyramine were 190.1 +/- 19.5 microM and 58.2 +/- 13.8 microM, respectively. Tyramine is an endogenous compound which exists in the brain as a trace amine but is also an exogenous compound which is found in foods such as cheese and wine. Our results suggest that dopamine is formed from endogenous and/or exogenous tyramine by this CYP2D isoform.

Animals↗
PubMed1985

Tyramine pressor sensitivity changes during deprenyl treatment.

Deprenyl has previously been reported to be a selective monoamine oxidase (MAO) type B inhibitor, which is associated with little or no enhancement of the pressor effects of tyramine. Employing an intravenous steady-state tyramine infusion technique, the effects of different doses of deprenyl and, for comparison, the mixed inhibitor tranylcypromine on the pressor response to tyramine were studied in 11 depressed patients. After 3 weeks of treatment, deprenyl produced dose-proportionate increases in tyramine sensitivity at all three doses (10, 30, and 60 mg/day) when compared to placebo baseline tyramine responses. While only a modest (3.7-fold) increase in tyramine sensitivity was found with the 10 mg/day deprenyl dose, the increase in tyramine sensitivity at the 60 mg/day dose of deprenyl (22-fold) approached that found with tranylcypromine. Reductions in plasma 3-methoxy,4-hydroxyphenylglycol (MHPG), used as a possible index of in vivo MAO-A inhibition, were highly correlated with increases in tyramine pressor sensitivity (r = 0.82). The data suggest that deprenyl acts as a relatively selective MAO-B inhibitor at low doses, but that this selectivity is lost at higher doses, resulting in a significant "crossover" inhibition of MAO-A and increased tyramine pressor sensitivity.

Blood Pressure↗
PubMed1982

Effects of tyramine on blood pressure and plasma catecholamines in normal and hypertensive subjects.

Responses of blood pressure and plasma catecholamines to intravenous injection of tyramine at increasing dosage (30, 45, and 60 microgram/kg, respectively) were evaluated in 25 normal subjects and 20 patients with mild essential hypertension. Basal plasma norepinephrine and epinephrine concentrations before tyramine injections were similar in the two groups. Following tyramine injection, plasma epinephrine was unchanged. Responses of plasma catecholamines and blood pressure to tyramine were similar in the two groups. Plasma norepinephrine increased significantly 2 min after a dose of 30 microgram/kg, but higher tyramine doses failed to produce a further increase in plasma norepinephrine. In contrast, pressor responses to tyramine were dose-dependent. Maximal pressor responses were observed within 23 min after injection. These findings reveal a dissociation between changes in blood pressure and plasma norepinephrine following injection of tyramine. Lack of steady state may limit the value of tyramine bolus injections as a tool for the quantitation of pressor responsiveness to variations in endogenous sympathetic output. Alternatively, it is possible that the pressor effect of tyramine may be mediated at least in part by a norepinephrine independent mechanism.

Adult↗
PubMed1987

Tyramine pressor response with moclobemide--a reversible monoamine oxidase inhibitor.

Moclobemide is a reversible, short-acting monoamine oxidase inhibitor (MAO1), specific for MAO A. To study moclobemide effects on the tyramine pressor response, we gave 12 depressed patients (2 males, 10 females; mean age 47, SD 11 years) an i.v. tyramine test after 7 days drug free. The mean (+/- SD) tyramine dose to raise systolic blood pressure 30 mmHg was 5.6 +/- 2.5 mg. Repeat tyramine testing after 2 weeks of treatment with moclobemide (280 +/- 90 mg/d) showed the tyramine dose required was reduced to 2.5 +/- 1.6 mg (n = 8). The mean (+/- SD) increase in sensitivity to tyramine was 2.9 +/- 1.8. Four patients did not have repeated tyramine tests as testing was discontinued because of tyramine-induced cardiac arrhythmias. Moclobemide seems an effective antidepressant with less tyramine sensitivity than MAOIs in current use.

Adult↗
PubMed2005

A new family of insect tyramine receptors.

The Drosophila Genome Project database contains a gene, CG7431, annotated to be an "unclassifiable biogenic amine receptor." We have cloned this gene and expressed it in Chinese hamster ovary cells. After testing various ligands for G protein-coupled receptors, we found that the receptor was specifically activated by tyramine (EC(50), 5x10(-7)M) and that it showed no cross-reactivity with beta-phenylethylamine, octopamine, dopa, dopamine, adrenaline, noradrenaline, tryptamine, serotonin, histamine, and a library of 20 Drosophila neuropeptides (all tested in concentrations up to 10(-5) or 10(-4)M). The receptor was also expressed in Xenopus oocytes, where it was, again, specifically activated by tyramine with an EC(50) of 3x10(-7)M. Northern blots showed that the receptor is already expressed in 8-hour-old embryos and that it continues to be expressed in all subsequent developmental stages. Adult flies express the receptor both in the head and body (thorax/abdomen) parts. In addition to the Drosophila tyramine receptor gene, CG7431, we found another closely related Drosophila gene, CG16766, that probably also codes for a tyramine receptor. Furthermore, we annotated similar tyramine-like receptor genes in the genomic databases from the malaria mosquito Anopheles gambiae and the honeybee Apis mellifera. These four tyramine or tyramine-like receptors constitute a new receptor family that is phylogenetically distinct from the previously identified insect octopamine/tyramine receptors. The Drosophila tyramine receptor is, to our knowledge, the first cloned insect G protein-coupled receptor that appears to be fully specific for tyramine.

Amino Acid Sequence↗
PubMed2006

Tyramine in the assessment of regional adrenergic function.

Regional adrenergic function is difficult to assess in humans. Tyramine given through a microdialysis probe may be a useful tool in this regard. However, tyramine data is hard to interpret given the drug's complex mode of action. We characterized the response to tyramine, isoproterenol, and dopamine in adipose tissue with microdialysis probes in normal subjects. We measured glycerol concentrations to follow changes in lipolysis and monitored tissue perfusion with ethanol dilution. During perfusion with tyramine, dialysate glycerol concentration increased dose-dependently from 83+/-8 microM at baseline to 181+/-18 microM at 3.5 mM tyramine (p<0.001) followed by a fall down to 121+/-9 microM at 35 mM tyramine (p<0.001). Propranolol almost completely blocked this response. A similar lipolytic response was not observed in isolated human adipocytes. Dopamine <35 microM did not replicate the tyramine-induced lipolysis; however, dopamine >35 microM potently inhibited lipolysis. We conclude that tyramine-induced lipolysis is explained by a pre-synaptic mechanism. Tyramine applied through a microdialysis probe in concentrations up to 3.5 mM can be used to assess pre- and post-synaptic mechanisms regulating lipid mobilization.

Adipocytes↗
PubMed1989

Conformationally restricted and conformationally defined tyramine analogues as inhibitors of phenylethanolamine N-methyltransferase.

In a search for a selective inhibitor for the epinephrine synthesizing enzyme phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28), phenolic 2-aminotetralins (12-15 as conformationally restricted analogues of tyramine) and phenolic benzobicyclo[3.2.1]octylamines (22-24 as conformationally defined analogues of tyramine) were used to gain information about the binding interactions of the catecholic hydroxyl groups in the natural substrate norepinephrine at the active site of PNMT. In addition, these analogues provided information about the effects of conformational flexibility on active-site interaction of the aminoethyl side chain in phenolic phenylethylamines that may aid in learning the manner in which norepinephrine binds at the active site of PNMT. Analogues 22-24 were synthesized by a nine-step sequence, in which a Friedel-Crafts type intramolecular cyclization was the key step in the construction of the benzobicyclo[3.2.1]octane skeleton. p-Tyramine (10, Ki = 294 microM) was more potent than phenylethylamine (1, Ki = 854 microM) but m-tyramine (9, Ki = 1250 microM) was less potent than phenylethylamine as an inhibitor of PNMT. Similarly, in the conformationally restricted and conformationally defined tyramine analogues (12-15 and 22-24, respectively), the analogues with the p-tyramine moiety (14, Ki = 4.7 microM; 23, Ki = 111 microM) bind to PNMT better than do the corresponding unsubstituted compounds (16, Ki = 6.8 microM; 25, Ki = 206 microM) while the analogues with the m-tyramine moiety (13, 15, 22, and 24) have a lower binding affinity than do 16 and 25. The greatly enhanced activity of the phenolic 2-aminotetralins (12-15) compared with m- and p-tyramine (9 and 10, respectively) is likely due to the restriction of the side-chain conformation. The conformationally defined analogues 22-24 were less active than the conformationally restricted ones, 12-15, although the low-energy half-chair conformation of 2-aminotetralin is defined in 22-24. The reduced activity of 22-24 compared with the activity of 12-15 is probably due to the steric hindrance from the extra bridging atoms in binding to PNMT. The interaction of the p-hydroxyl group of the tyramine moiety may involve hydrogen bonding since the corresponding methyl ethers show a greatly reduced affinity for the active site of PNMT (Ki = 34 and 389 microM for methoxy analogues 28 and 35, compared to Ki = 4.7 and 111 microM for the corresponding phenolic analogues 14 and 23).

Molecular Conformation↗
PubMed1997

Detoxication of tyramine by the flavin-containing monooxygenase: stereoselective formation of the trans oxime.

In the presence of pig or adult human liver microsomes, tyramine was metabolized to the corresponding trans oxime through the intermediacy of the hydroxylamine. The requisite intermediate, (4-hydroxyphenethyl)hydroxylamine, was retroreduced to tyramine or converted stereoselectively to the trans oxime in the presence of pig or adult human liver microsomes. Studies of the effect of metabolic inhibitors suggested that formation of the trans oxime and retroreduction of the hydroxylamine were largely dependent on NADPH and the flavin-containing monooxygenase (FMO) and cytochrome P450, respectively. The conclusion that FMO was predominantly responsible for trans oxime formation in human liver microsomes was based on the effect of incubation conditions on tyramine N-oxygenation and the observation that cDNA-expressed human FMO3 also N-oxygenated tyramine to give exclusively the trans oxime. The synthetic hydroxylamine and oxime metabolites of tyramine were examined for affinity to human and animal dopamine and serotonin receptors and the human dopamine transporter. For all of the receptors and for the transporter examined, the avidity of the hydroxylamine and oximes was greater than 10 microM and beyond the effective concentration for physiological relevance. The results suggested that tyramine was sequentially N-oxygenated in the presence of pig and human liver microsomes and cDNA-expressed FMO3 to the hydroxylamine and then to the di-N-hydroxylamine that was spontaneously dehydrated to the trans oxime. This may be facilitated by FMO through a nondissociative substrate-enzyme interaction. Based on the biogenic amine receptor or transporter affinity for the hydroxylamine and oxime metabolites of tyramine, N-oxygenation of tyramine by pig or human liver FMO may represent a detoxication reaction that terminates the pharmacological activity of tyramine.

Adult↗
PubMed1992

Pharmacokinetic and pharmacodynamic interaction between toloxatone, a new reversible monoamine oxidase-A inhibitor, and oral tyramine in healthy subjects.

We examined the influence of toloxatone, a new reversible monoamine oxidase-A inhibitor used in the treatment of depression, on tyramine-induced pressor effect in healthy volunteers. The maximum increase in systolic blood pressure produced by four single oral doses of tyramine administered during a meal and ranging from 100 mg to 800 mg was compared during repeated (3 to 5 days) administration of placebo, 200 mg toloxatone three times a day and 400 mg toloxatone three times a day in a single-blind, three-period crossover study. Toloxatone by itself had no significant influence on blood pressure. During administration of toloxatone, no significant increase in tyramine-induced increase in systolic blood pressure was observed for tyramine doses of 200 mg or less that are consistently higher than those associated with normal food intake. However, toloxatone increased the tyramine-induced increase in blood pressure after 400 mg tyramine (400 mg toloxatone three times a day) and 800 mg tyramine (200 mg toloxatone three times a day and 400 mg toloxatone three times a day). This pharmacodynamic interaction could be explained by an increase in tyramine systemic bioavailability in the presence of toloxatone. It is concluded that interaction between tyramine in meals and toloxatone is unlikely to occur in patients after long-term administration of the drug at therapeutic dosages.

Administration, Oral↗
PubMed1981

Effects of caroxazone, a reversible monoamine oxidase inhibitor, on the pressor response to oral tyramine in man.

1 A double-blind, placebo-controlled study was carried out in order to investigate the effects of caroxazone, a new antidepressant drug endowed with a reversible short-lasting MAO-inhibitory activity in man, on the blood pressure response to tyramine administered by the oral route. 2 The study was carried out in 9 healthy volunteers who were randomly assigned to treatment with caroxazone 200 mg three times daily (7 subjects) or with indistinguishable placebo (2 subjects). 3 The sensitivity to tyramine was assessed in each subject both before and after the 7-9 days of treatment. 4. While placebo did not modify the pressor response to tyramine, the threshold dose of tyramine which induced a rise in systolic blood pressure was lowered by about four-fold in 6 out of the 7 subjects treated with caroxazone. In the seventh subject the observed potentiation of peroral tyramine was not quantitatively evaluable. 5 Challenges performed in three subjects after discontinuation of treatment with caroxazone show that the effects of the compound are short-lasting, since the sensitivity to tyramine seems to regain the baseline value within 1-2 days. 6 Even if caroxazone potentiates peroral tyramine to a relatively low degree, a tyramine poor diet is recommended for patients during caroxazone treatment. 7 The reversibility of the MAO-inhibitory action of caroxazone is confirmed by the rapid return to normal values in the response to tyramine after discontinuation of treatment. This property of caroxazone would allow patients to return to a free diet in much less time than the safety limit of 2 weeks recommended for the currently used irreversible MAO-inhibitors.

Adult↗
PubMed2005

TYRA-2 (F01E11.5): a Caenorhabditis elegans tyramine receptor expressed in the MC and NSM pharyngeal neurons.

Tyramine appears to regulate key processes in nematodes, such as pharyngeal pumping, and more complex behaviors, such as foraging. Recently, a Caenorhabditis elegans tyramine receptor, SER-2, was identified that is involved in the TA-dependent regulation of these processes. In the present study, we have identified a second C. elegans gene, tyra-2 (F01E11.5) that encodes a tyramine receptor. This is the first identification of multiple tyramine receptor genes in any invertebrate. Membranes from COS-7 cells expressing TYRA-2 bind [(3)H]tyramine with high affinity with a K(d) of 20 +/- 5 nM. Other physiologically relevant biogenic amines, such as octopamine and dopamine, inhibit [(3)H]tyramine binding with much lower affinity (K(i)s of 1.55 +/- 0.5 and 1.78 +/- 0.6 microM, respectively), supporting the identification of TYRA-2 as a tyramine receptor. Indeed, tyramine also dramatically increases GTPgammaS binding to membranes from cells expressing TYRA-2 (EC(50) of 50 +/- 13 nM) and the TA-dependent GTPgammaS binding is PTX-sensitive suggesting that TYRA-2 may couple to Galpha(i/o). Based on fluorescence from tyra::gfp fusion constructs, TYRA-2 expression appears to be exclusively neuronal in the MC and NSM pharyngeal neurons, the AS family of amphid neurons and neurons in the nerve ring, body and tail. Taken together, these results suggest that TYRA-2 encodes a second Galpha(i/o)-coupled tyramine receptor and suggests that TA-dependent neuromodulation may be mediated by multiple receptors and more complex than previously appreciated.

Amino Acid Sequence↗