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Terho Lehtimäki - One of the best experts on this subject based on the ideXlab platform.

  • TPH1 a218c polymorphism and temperament in major depression
    BMC Psychiatry, 2013
    Co-Authors: Kadri Andre, Olli Kampman, Merja Viikki, Outi Poutanen, Nina Mononen, Esa Leinonen, Ari Illi, Eija Setalasoikkeli, Terho Lehtimäki
    Abstract:

    In major depression, one of the candidate genes possibly affecting the risk and severity of symptoms has been found to be tryptophan hydroxylase (TPH1). Variation in treatment response to antidepressive agents according to TPH1 genotype has also been found in several studies. However, the relationship between temperament and TPH1 genotype in major depression is poorly understood, as only one study has been published so far. There are no earlier studies on the interaction between temperament traits, antidepressive medication response and TPH1 genotype. This interaction was studied in 97 subjects with major depression treated for six weeks with selective serotonine reuptake inhibitors. Temperament dimensions Harm Avoidance (HA), Novelty Seeking (NS), Reward Dependence (RD) and Persistence (P) scores at baseline (1) and endpoint (2) were rated with the Temperament and Character Inventory (TCI) and compared between TPH1 A218C genotypes. Multivariate analysis of co-variance (MANCOVA) was used to analyze the interaction between the TPH1 genotype, treatment response and the different temperament dimensions at baseline and endpoint. In the analysis model, treatment response was used as a covariate and TPH1 genotype as a factor. A post hoc analysis for an interaction between remission status and TPH1 A218C genotype at endpoint HA level was also performed. The number of TPH1 A-alleles was associated with increasing levels in NS1 and NS2 scores and decreasing levels in HA1 and HA2 scores between TPH1 A218C genotypes. In the MANCOVA model, TPH1 genotype and treatment response had an interactive effect on both HA1 and HA2 scores, and to a lesser degree on NS2 scores. Additionally, an interaction between remission status and TPH1 A218C genotype was found to be associated with endpoint HA score, with a more marked effect of the interaction between CC genotype and remission status compared to A-allele carriers. Our results suggest that in acute depression TPH1 A218C polymorphism and specifically the CC genotype together with the information on remission or treatment response differentiates between different temperament profiles and their changes.

  • 5-HTR1A, 5-HTR2A, 5-HTR6, TPH1 and TPH2 polymorphisms and major depression.
    Neuroreport, 2009
    Co-Authors: Ari Illi, Eija Setälä-soikkeli, Merja Viikki, Outi Poutanen, Nina Mononen, Terho Lehtimäki, Esa Leinonen, Heini Huhtala, Olli Kampman
    Abstract:

    Genes that regulate the serotonin signalling system are potential targets for research in the aetiology of mood disorders and also in the treatment response of serotonin reuptake inhibitors. In this study, we evaluated the association of seven serotonin signal transduction-linked single nucleotide polymorphisms [HTR1A (rs6295), HTR2A (rs6313, rs6311 and rs7997012), HTR6 (rs1805054), TPH1 (rs1800532) and TPH2 (rs1386494)] with major depressive disorder and/or treatment outcome with serotonin reuptake inhibitors. Patients who met the criteria for major depressive disorder were treated for 6 weeks with fluoxetine, paroxetine or citalopram. The treatment response was evaluated with the Montgomery-Asberg Depression Rating Scale, and according to predefined response criteria, the patients were divided into responders, nonresponders, remitters and nonremitters. Altogether, 86 patients completed the entire study according to the study protocol. We had also a control population (N = 395) of healthy blood donors. None of the seven single nucleotide polymorphisms was associated with major depressive disorder or with treatment response in our study population of Finnish individuals.

  • tryptophan hydroxylase 1 gene TPH1 moderates the influence of social support on depressive symptoms in adults
    Journal of Affective Disorders, 2007
    Co-Authors: Markus Jokela, Terho Lehtimäki, Riikka Rontu, Katri Raikkonen, Liisa Keltikangasjarvinen
    Abstract:

    Abstract Background Tryptophan hydroxylases (TPHs) are involved in the biosynthesis of serotonin and are therefore candidate genes for psychiatric disorders, including depression. We examined whether the common 218 A > C and 779 A > C polymorphisms in the tryptophan hydroxylase 1 gene (TPH1) moderated the association between perceived social support and sub-clinical depressive symptoms in adults. Methods The subjects were a randomly selected subsample ( n  = 341) of individuals participating in the Cardiovascular Risk in Young Finns study, who had data on social support on one assessment time and depressive symptoms on two assessment times. Social support was assessed on the Perceived Social Support Scale Revised (PSSS-R) and depressive symptoms on a modified version of the Beck's Depression Inventory (BDI). Results We found that low social support predicted depressive symptoms more strongly in individuals carrying A alleles of the TPH1 than in others. The interaction effect was observed in a cross-sectional analysis and when predicting depressive symptoms over a four-year period. Limitations We did not have data on TPH2, which has recently been identified as the primary TPH isomorphism affecting serotonin synthesis in the brain. Conclusions TPH1 gene may be involved in the development of depressive symptoms by moderating the impact of depressogenic social influences.

  • research report tryptophan hydroxylase 1 gene TPH1 moderates the influence of social support on depressive symptoms in adults
    2007
    Co-Authors: Markus Jokela, Terho Lehtimäki, Riikka Rontu, Katri Raikkonen, Liisa Keltikangasjarvinen
    Abstract:

    Background: Tryptophan hydroxylases (TPHs) are involved in the biosynthesis of serotonin and are therefore candidate genes for psychiatric disorders, including depression. We examined whether the common 218 A N C and 779 A N C polymorphisms in the tryptophan hydroxylase 1 gene (TPH1) moderated the association between perceived social support and sub-clinical depressive symptoms in adults. Methods: The subjects were a randomly selected subsample (n=341) of individuals participating in the Cardiovascular Risk in Young Finns study, who had data on social support on one assessment time and depressive symptoms on two assessment times. Social support was assessed on the Perceived Social Support Scale Revised (PSSS-R) and depressive symptoms on a modified version of the Beck's Depression Inventory (BDI). Results: We found that low social support predicted depressive symptoms more strongly in individuals carrying A alleles of the TPH1 than in others. The interaction effect was observed in a cross-sectional analysis and when predicting depressive symptoms over a four-year period. Limitations: We did not have data on TPH2, which has recently been identified as the primary TPH isomorphism affecting serotonin synthesis in the brain. Conclusions: TPH1 gene may be involved in the development of depressive symptoms by moderating the impact of depressogenic social influences.

  • Interaction between TPH1 and GNB3 genotypes and electroconvulsive therapy in major depression
    Journal of neural transmission (Vienna Austria : 1996), 2006
    Co-Authors: Sami Anttila, Esa Leinonen, Kaija Huuhka, Martti Huuhka, Riikka Rontu, Kari M. Mattila, Terho Lehtimäki
    Abstract:

    We studied the association between tryptophan hydroxylase 1 (TPH1) A218C and G-protein beta-3 subunit (GNB3) C825T polymorphisms and treatment response in electroconvulsive therapy (ECT). The sample consisted of 119 patients with major depressive disorder (MDD) and 398 controls. Neither TPH1 nor GNB3 polymorphisms are associated with treatment response. However, subjects carrying TPH1 CC genotype are more likely to belong to the patient sample than to the controls. In female subjects, T-allele of GNB3 polymorphism increases the risk of being a treatment-resistant patient with MDD. Moreover, in females the combination of TPH1 CC and GNB3 CT + TT genotype is associated with an increased risk of belonging to the patient group.

Michael Bader - One of the best experts on this subject based on the ideXlab platform.

  • Altered Gene Expression in Pulmonary Tissue of Tryptophan Hydroxylase-1 Knockout Mice: Implications for Pulmonary Arterial Hypertension
    2013
    Co-Authors: Richard B. Rothman, Michael Bader, Jean L. Cadet, Christina M. Dersch, Michael T. Mccoy, Elin Lehrmann, Kevin G, Natalia Alenina, Michael H. Baumann
    Abstract:

    The use of fenfluramines can increase the risk of developing pulmonary arterial hypertension (PAH) in humans, but the mechanisms responsible are unresolved. A recent study reported that female mice lacking the gene for tryptophan hydroxylase-1 (TPH1(2/2) mice) were protected from PAH caused by chronic dexfenfluramine, suggesting a pivotal role for peripheral serotonin (5-HT) in the disease process. Here we tested two alternative hypotheses which might explain the lack of dexfenfluramine-induced PAH in TPH1(2/2) mice. We postulated that: 1) TPH1(2/2) mice express lower levels of pulmonary 5-HT transporter (SERT) when compared to wild-type controls, and 2) TPH1(2/2) mice display adaptive changes in the expression of non-serotonergic pulmonary genes which are implicated in PAH. SERT was measured using radioligand binding methods, whereas gene expression was measured using microarrays followed by quantitative real time PCR (qRT-PCR). Contrary to our first hypothesis, the number of pulmonary SERT sites was modestly up-regulated in female TPH1(2/2) mice. The expression of 51 distinct genes was significantly altered in the lungs of female TPH1(2/2) mice. Consistent with our second hypothesis, qRT-PCR confirmed that at least three genes implicated in the pathogenesis of PAH were markedly up-regulated: Has2, Hapln3 and Retlna. The finding that female TPH1(2/2) mice are protected from dexfenfluramineinduced PAH could be related to compensatory changes in pulmonary gene expression, in addition to reductions i

  • influence of human tryptophan hydroxylase 2 n and c terminus on enzymatic activity and oligomerization
    Journal of Neurochemistry, 2007
    Co-Authors: Katja Tenner, Diego J Walther, Michael Bader
    Abstract:

    Tryptophan hydroxylase (TPH) catalyses the first and rate limiting step in the biosynthesis of the neurotransmitter serotonin. There are two TPH isoenzymes in humans, encoded by two different genes: TPH1 and the recently described TPH2. We have expressed both human enzymes and various deletion mutants of TPH2 (DeltaN44, DeltaC17, DeltaC19, DeltaC51) in COS7 cells. TPH1 and 2 displayed different kinetic properties with a lower K(m) value of TPH1. Removal of 44 amino acids from the N-terminus of TPH2 resulted in a 3-4-fold increased V(max), which indicates a strong inhibitory function of this part on the enzymes activity. TPH1 and 2 were able to form homooligomers and also heterooligomers with each other. The different deletion mutants (DeltaC17, DeltaC19 and DeltaC51), which lack the putative C-terminal leucine zipper tetramerization domain, existed as monomeric enzymes. While short deletions (DeltaC17 and DeltaC19) hardly changed V(max) values, the DeltaC51 mutant lost 99% of TPH activity. These data identify a region between the C-terminal oligomerization domain and the catalytic domain, which is indispensable for TPH2 activity.

  • norfenfluramine induced arterial contraction is not dependent on endogenous 5 hydroxytryptamine or 5 hydroxytryptamine transporter
    Journal of Pharmacology and Experimental Therapeutics, 2005
    Co-Authors: Claudia S. Wilhelm, Michael Bader, Dennis L. Murphy, Keith J. Lookingland, Stephanie W. Watts
    Abstract:

    (+)-Norfenfluramine, the major metabolite of fenfluramine, causes vasoconstriction dependence on the 5-hydroxytryptamine (5-HT)2A receptor in rat. (+)-Norfenfluramine was reported as a 5-hydroxytryptamine transporter (5-HTT) substrate and 5-HT releaser. Because the arterial 5-HTT exists and is functional in the rat, we hypothesized that (+)-norfenfluramine causes vasoconstriction by releasing 5-HT from vascular smooth muscle via 5-HTT. The released 5-HT, in turn, activates the 5-HT2A receptor. Isometric contractility experiments showed that (+)-norfenfluramine-induced mouse aortic contraction was reduced by the 5-HTT inhibitor fluoxetine (1 μM) but not by fluvoxamine (1 μM). Tryptophan hydroxylase (TPH)-deficient ( TPH1 – / –) mice lack peripheral 5-HT. (+)-Norfenfluramine (10 nM–100 μM)-contracted aorta from wild-type and TPH1 –/– mice with equivalent potency (–log EC50 [M], wild type = 5.73 ± 0.02, TPH1 –/– = 5.62 ± 0.09), and these contractions were inhibited by the 5-HT2A receptor antagonist ketanserin (3 nM) by a similar magnitude in aorta from wild-type and TPH1 –/– mice (wild type = 19.4, TPH1 –/– = 15.4-fold rightward shift versus control), as did fluoxetine (1 μM) (wild type = 22.4, TPH1 –/– = 28.8-fold rightward shift versus control). To further test the role of 5-HTT in (+)-norfenfluramine-induced aortic contraction, the 5-HTT-targeted mutation mouse was used. (+)-Norfenfluramine induced similar aortic contraction in wild-type and 5-HTT-targeted mutation mice, and these contractions were inhibited by fluoxetine (1 μM). Thus, (+)-norfenfluramine vasoconstriction is not dependent on 5-HTT-mediated release of endogenous 5-HT but by activating membrane 5-HT2A receptors directly. Understanding of the mechanism by which (+)-norfenfluramine induces vasoconstriction is important to characterize and understand the function of the serotonergic system in peripheral arterial vasculature.

Alexander G Tonevitsky - One of the best experts on this subject based on the ideXlab platform.

  • latrophilin 1 and its endogenous ligand lasso teneurin 2 form a high affinity transsynaptic receptor pair with signaling capabilities
    Proceedings of the National Academy of Sciences of the United States of America, 2011
    Co-Authors: Johnpaul Silva, Vera G Lelianova, Yaroslav S Ermolyuk, Nickolai Vysokov, Paul G Hitchen, Otto Berninghausen, Atiqur M Rahman, Alice Zangrandi, Sara Fidalgo, Alexander G Tonevitsky
    Abstract:

    Latrophilin 1 (LPH1), a neuronal receptor of α-latrotoxin, is implicated in neurotransmitter release and control of presynaptic Ca2+. As an “adhesion G-protein-coupled receptor,” LPH1 can convert cell surface interactions into intracellular signaling. To examine the physiological functions of LPH1, we used LPH1’s extracellular domain to purify its endogenous ligand. A single protein of ∼275 kDa was isolated from rat brain and termed Lasso. Peptide sequencing and molecular cloning have shown that Lasso is a splice variant of teneurin-2, a brain-specific orphan cell surface receptor with a function in neuronal pathfinding and synaptogenesis. We show that LPH1 and Lasso interact strongly and specifically. They are always copurified from rat brain extracts. Coculturing cells expressing LPH1 with cells expressing Lasso leads to their mutual attraction and formation of multiple junctions to which both proteins are recruited. Cells expressing LPH1 form chimerical synapses with hippocampal neurons in cocultures; LPH1 and postsynaptic neuronal protein PSD-95 accumulate on opposite sides of these structures. Immunoblotting and immunoelectron microscopy of purified synapses and immunostaining of cultured hippocampal neurons show that LPH1 and Lasso are enriched in synapses; in both systems, LPH1 is presynaptic, whereas Lasso is postsynaptic. A C-terminal fragment of Lasso interacts with LPH1 and induces Ca2+ signals in presynaptic boutons of hippocampal neurons and in neuroblastoma cells expressing LPH1. Thus, LPH1 and Lasso can form transsynaptic complexes capable of inducing presynaptic Ca2+ signals, which might affect synaptic functions.

Donald M Kuhn - One of the best experts on this subject based on the ideXlab platform.

  • phosphorylation and activation of tryptophan hydroxylase 2 identification of serine 19 as the substrate site for calcium calmodulin dependent protein kinase ii
    Journal of Neurochemistry, 2007
    Co-Authors: Donald M Kuhn, Stacey A Sakowski, Timothy J Geddes, Curtis G Wilkerson, John W Haycock
    Abstract:

    Tryptophan hydroxylase (TPH) is the initial and rate-limiting enzyme in the biosynthesis of serotonin. TPH was once thought to be a single-gene product but it is now known to exist in two isoforms. TPH1 is found in the periphery and pineal gland whereas TPH2 is expressed specifically in the CNS. Both TPH isoforms are known to be regulated by protein kinase-dependent phosphorylation and the sites of modification of TPH1 by protein kinase A have been identified. While TPH2 is activated by calcium, calmodulin-dependent protein kinase II (CaMKII), the sites at which this isoform is modified are not known. Treatment of wild-type TPH2 with CaMKII followed by mass spectrometry analysis revealed that the enzyme was activated and phosphorylated at a single site, serine-19. Mutagenesis of serine-19 to alanine did not alter the catalytic function of TPH2 but this mutant enzyme was neither activated nor phosphorylated by CaMKII. A phosphopeptide bracketing phosphoserine-19 in TPH2 was used as an antigen to generate polyclonal antibodies against phosphoserine-19. The antibodies are highly specific for phosphoserine-19 in TPH2. The antibodies do not react with wild-type TPH2 or TPH1 and they do not recognize phophoserine-58 or phosphoserine-260 in TPH1. These results establish that activation of TPH2 by CaMKII is mediated by phosphorylation of serine-19 within the regulatory domain of the enzyme. Production of a specific antibody against the CaMKII phosphorylation site in TPH2 represents a valuable tool to advance the study of the mechanisms regulating the function of this important enzyme.

  • differential tissue distribution of tryptophan hydroxylase isoforms 1 and 2 as revealed with monospecific antibodies
    Brain Research, 2006
    Co-Authors: Stacey A Sakowski, Timothy J Geddes, David M Thomas, Edi Levi, James S Hatfield, Donald M Kuhn
    Abstract:

    Abstract Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of the neurotransmitter serotonin. Once thought to be a single-gene product, TPH is now known to exist in two isoforms—TPH1 is found in the pineal and gut, and TPH2 is selectively expressed in brain [Walther, D.J., Peter, J.U., Bashammakh, S., Hortnagl, H., Voits, M., Fink, H., Bader, M., 2003. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299, 76.]. Heretofore, probes used for localization of TPH protein or mRNA could not distinguish between the TPH isoforms because of extensive homology shared by them at the nucleotide and amino acid level. We have produced monospecific polyclonal antibodies against TPH1 and TPH2 using peptide antigens from nonoverlapping sequences in the respective proteins. These antibodies allow the differentiation of TPH1 and TPH2 upon immunoblotting, immunoprecipitation, and immunocytochemical staining of tissue sections from brain and gut. TPH1 and TPH2 antibodies do not cross-react with either tyrosine hydroxylase or phenylalanine hydroxylase. Analysis of mouse tissues confirms that TPH1 is the predominant form expressed in pineal gland and in P815 mastocytoma cells with a molecular weight of 51 kDa. TPH2 is the predominant enzyme form expressed in brain extracts from mesencephalic tegmentum, striatum, and hippocampus with a molecular weight of 56 kDa. Antibody specificity against TPH1 and TPH2 is retained across mouse, rat, rabbit, primate, and human tissues. Antibodies that distinguish between the isoforms of TPH will allow studies of the differential regulation of their expression in brain and periphery.

  • mouse tryptophan hydroxylase isoform 2 and the role of proline 447 in enzyme function
    Journal of Neurochemistry, 2006
    Co-Authors: Stacey A Sakowski, Donald M Kuhn, Timothy J Geddes
    Abstract:

    Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of the neurotransmitter serotonin (5-HT). Once thought to be a single gene product, TPH is now known to exist in two isoforms. Isoform 1 (TPH1) is found in the pineal gland and gut, and isoform 2 (TPH2) is selectively expressed in brain. A single-nucleotide polymorphism in TPH2 results in a proline-to-arginine mutation at residue 447 and substantially lowers catalytic activity. In view of the importance of TPH in determining brain 5-HT function, we cloned TPH2 and produced the P447R mutant to assess the importance of this proline in enzyme function. Catalytically active TPH2 and the P447R mutant were expressed at the predicted subunit molecular mass of 56 kDa. The P447R mutant expressed less than 50% of the activity of TPH2. Mutation of this conserved proline in TPH1 (P403R) also resulted in an enzyme with significantly lower activity than the wild-type enzyme. The P447R mutant had a Vmax 50% lower than that of TPH2. The P447R mutation did not alter the oligomeric assembly of the protein, nor change its responsiveness to cysteine modification. The P447R mutation did not alter enzyme substrate specificity or stability, but conferred slightly enhanced sensitivity to inhibition by dopamine and diminished sensitivity to iron in catalysis. The conserved proline in TPH (residue 447 in TPH2 and 403 in TPH1) plays an important role in enzyme function by regulating Vmax of the catalytic reaction.

Purna C Kashyap - One of the best experts on this subject based on the ideXlab platform.

  • gut microbes promote colonic serotonin production through an effect of short chain fatty acids on enterochromaffin cells
    The FASEB Journal, 2015
    Co-Authors: Christopher S Reigstad, Charles E Salmonson, John F Rainey, J H Szurszewski, David R Linden, Justin L Sonnenburg, Gianrico Farrugia, Purna C Kashyap
    Abstract:

    Gut microbiota alterations have been described in several diseases with altered gastrointestinal (GI) motility, and awareness is increasing regarding the role of the gut microbiome in modulating GI function. Serotonin [5-hydroxytryptamine (5-HT)] is a key regulator of GI motility and secretion. To determine the relationship among gut microbes, colonic contractility, and host serotonergic gene expression, we evaluated mice that were germ-free (GF) or humanized (HM; ex-GF colonized with human gut microbiota). 5-HT reduced contractile duration in both GF and HM colons. Microbiota from HM and conventionally raised (CR) mice significantly increased colonic mRNAs TPH1 [(tryptophan hydroxylase) 1, rate limiting for mucosal 5-HT synthesis; P < 0.01] and chromogranin A (neuroendocrine secretion; P < 0.01), with no effect on monoamine oxidase A (serotonin catabolism), serotonin receptor 5-HT4, or mouse serotonin transporter. HM and CR mice also had increased colonic TPH1 protein (P < 0.05) and 5-HT concentrations (GF, 17 ± 3 ng/mg; HM, 25 ± 2 ng/mg; and CR, 35 ± 3 ng/mg; P < 0.05). Enterochromaffin (EC) cell numbers (cells producing 5-HT) were unchanged. Short-chain fatty acids (SCFAs) promoted TPH1 transcription in BON cells (human EC cell model). Thus, gut microbiota acting through SCFAs are important determinants of enteric 5-HT production and homeostasis.

  • gut microbes promote colonic serotonin production through an effect of short chain fatty acids on enterochromaffin cells
    The FASEB Journal, 2015
    Co-Authors: Christopher S Reigstad, Charles E Salmonson, John F Rainey, J H Szurszewski, David R Linden, Justin L Sonnenburg, Gianrico Farrugia, Purna C Kashyap
    Abstract:

    Gut microbiota alterations have been described in several diseases with altered gastrointestinal (GI) motility, and awareness is increasing regarding the role of the gut microbiome in modulating GI function. Serotonin [5-hydroxytryptamine (5-HT)] is a key regulator of GI motility and secretion. To determine the relationship among gut microbes, colonic contractility, and host serotonergic gene expression, we evaluated mice that were germ-free (GF) or humanized (HM; ex-GF colonized with human gut microbiota). 5-HT reduced contractile duration in both GF and HM colons. Microbiota from HM and conventionally raised (CR) mice significantly increased colonic mRNAs TPH1 [(tryptophan hydroxylase) 1, rate limiting for mucosal 5-HT synthesis; P < 0.01] and chromogranin A (neuroendocrine secretion; P < 0.01), with no effect on monoamine oxidase A (serotonin catabolism), serotonin receptor 5-HT4, or mouse serotonin transporter. HM and CR mice also had increased colonic TPH1 protein (P < 0.05) and 5-HT concentrations (...