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Akira Takeshita - One of the best experts on this subject based on the ideXlab platform.
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Dual regulation of L-type Ca2+ channels by Serotonin 2 Receptor stimulation in vascular smooth muscle cells.
American Journal of Physiology-Heart and Circulatory Physiology, 1995Co-Authors: Youji Hirakawa, Takeshi Kuga, Sei Kobayashi, Hideo Kanaide, Akira TakeshitaAbstract:The purpose of the present study was to investigate regulation of voltage-dependent Ca2+ channels by Serotonin in rat aortic smooth muscle cells in primary culture. L- and T-type Ca2+ currents (ICa...
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Dual regulation of L-type Ca2+ channels by Serotonin 2 Receptor stimulation in vascular smooth muscle cells.
The American journal of physiology, 1995Co-Authors: Youji Hirakawa, Takeshi Kuga, Sei Kobayashi, Hideo Kanaide, Akira TakeshitaAbstract:The purpose of the present study was to investigate regulation of voltage-dependent Ca2+ channels by Serotonin in rat aortic smooth muscle cells in primary culture. L- and T-type Ca2+ currents (ICa) were recorded using the whole cell voltage-clamp method. Without pretreatment, in 25 of 30 cells examined, 10 microM Serotonin decreased L-type ICa to various extents (-14 to -72%). However, in the remaining five cells, Serotonin increased L-type ICa 21 +/- 4%. Thus, in 30 cells, Serotonin decreased L-type ICa an average of 22 +/- 5%. In the presence of intracellular heparin (100 micrograms/ml), a blocker of inositol 1,4,5-trisphosphate binding to its Receptor, Serotonin increased L-type ICa in all cells 29 +/- 3% (n = 6). When stored Ca2+ was depleted by pretreatment either with 20 microM ryanodine and 20 mM caffeine or with 100 nM A-23187, Serotonin also increased L-type ICa in all cells 30 +/- 5 (n = 4) or 37 +/- 5% (n = 12), respectively. In the presence of heparin, the Serotonin-induced increase of L-type ICa was prevented by 100 nM staurosporine (2 +/- 3%; n = 6, P < 0.01). The Serotonin-induced decrease of L-type ICa was significantly augmented by 100 nM staurosporine (-43 +/- 10%; n = 5). Phorbol 12,13-dibutylate (PDBu; 1 microM) increased L-type ICa 29 +/- 3% (n = 6), and Serotonin did not further increase L-type ICa after its potentiation by PDBu.(ABSTRACT TRUNCATED AT 250 WORDS)
R D Ciaranello - One of the best experts on this subject based on the ideXlab platform.
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Transcriptional control of the rat Serotonin-2 Receptor gene.
Molecular Brain Research, 1995Co-Authors: S J Garlow, R D CiaranelloAbstract:Abstract Previous reports have indicated that, in vivo, the Serotonin-2 (5-HT 2 ) Receptor is responsive to exogenously administered glucocorticoids. The ability of the glucocorticoid Receptor (GR) to influence transcription of the rat 5-HT 2 Receptor gene was tested in two different experimental paradigms. In both sets of experiments transcription of the 5-HT 2 gene was monitored with a promoter-reporter plasmid in which the promoter for the 5-HT 2 gene was driving the expression of the firefly luciferase gene. In the first, the 5-HT 2 promoter-reporter plasmid was transfected directly into RS1 cells followed by dexamethasone treatment. In the second set of experiments, the cDNA encoding the GR carried on a separate expression vector was cotransfected into CCL-39 or Neuro-2a cells along with the 5-HT 2 promoter-reporter plasmid. These cells were then exposed to dexamethasone. In the RS-1 and CCL-39 transfection experiments, the dexamethasone treatment caused an inhibition of transcription of the 5-HT 2 promoter, whereas in the Neuro-2a cells, the dexamethasone treatment stimulated transcription from the 5-HT 2 promoter. These responses were dependent on the presence of the GR. The effect of the activated GR would seem to be indirect as sequence analysis of the 4.2 kb preceding the site of transcription initiation revealed only an 11/15 nt match to a putative glucocorticoid response element (GRE), and deletion of this sequence did not alter the response to dexamethasone. Sequence analysis revealed a variety of potential response elements for other known transcription factors, including four potential AP-1 response elements. To examine the functionality of these response elements, the components of the AP-1 complex, c-Fos and c-Jun were tested separately and in combination as AP-1 for their ability to influence transcription of the 5-HT 2 promoter-reporter plasmid. Cell-selective enhancement or suppression by c-Fos and c-Jun of 5-HT 2 transcription was observed in these experiments.
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Transcriptional control of the rat Serotonin-2 Receptor gene.
Brain research. Molecular brain research, 1995Co-Authors: S J Garlow, R D CiaranelloAbstract:Previous reports have indicated that, in vivo, the Serotonin-2 (5-HT2) Receptor is responsive to exogenously administered glucocorticoids. The ability of the glucocorticoid Receptor (GR) to influence transcription of the rat 5-HT2 Receptor gene was tested in two different experimental paradigms. In both sets of experiments transcription of the 5-HT2 gene was monitored with a promoter-reporter plasmid in which the promoter for the 5-HT2 gene was driving the expression of the firefly luciferase gene. In the first, the 5-HT2 promoter-reporter plasmid was transfected directly into RS1 cells followed by dexamethasone treatment. In the second set of experiments, the cDNA encoding the GR carried on a separate expression vector was cotransfected into CCL-39 or Neuro-2a cells along with the 5-HT2 promoter-reporter plasmid. These cells were then exposed to dexamethasone. In the RS-1 and CCL-39 transfection experiments, the dexamethasone treatment caused an inhibition of transcription of the 5-HT2 promoter, whereas in the Neuro-2a cells, the dexamethasone treatment stimulated transcription from the 5-HT2 promoter. These responses were dependent on the presence of the GR. The effect of the activated GR would seem to be indirect as sequence analysis of the 4.2 kb preceding the site of transcription initiation revealed only an 11/15 nt match to a putative glucocorticoid response element (GRE), and deletion of this sequence did not alter the response to dexamethasone. Sequence analysis revealed a variety of potential response elements for other known transcription factors, including four potential AP-1 response elements.(ABSTRACT TRUNCATED AT 250 WORDS)
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Cloning and functional promoter mapping of the rat Serotonin-2 Receptor gene.
Molecular and cellular neurosciences, 1994Co-Authors: S J Garlow, Allison C. Chin, Adrian Marinovich, Mark R. Heller, R D CiaranelloAbstract:Abstract We have cloned the gene encoding the rat Serotonin-2 (5-HT2) Receptor. The transcription unit is divided into three exons by two introns. The major 5-HT2 transcript is 5.62 kb in length and contains 1173 bases of 5′-untranslated region (5′-UTR) 1413 bases of open reading frame, and 3033 bases of 3′-UTR. Primer extension demonstrates one strong transcription initiation site 1173 nt from the start codon. Reverse transcriptase-polymerase chain reaction analysis indicates the presence of at least one additional minor site of transcription initiation 1355 nt from the start codon. There are ATA boxes 28 nt 5′ to both the major and minor sites of transcription initiation, Functional promoter mapping was carried out in a transient transfection assay. This analysis reveals that there are negative attenuating elements between 2.5 and 2.3 kb from the initiation site and positive elements between 1100 and 200 nt from transcription initiation. Minimal promoter sequences are contained within 200 nt of the major site of transcription initiation. These findings suggest that the expression of the 5-HT2 Receptor gene is regulated by a combination of positive and negative elements operating through the minimal promoter.
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Immunocytochemical localization and description of neurons expressing Serotonin2 Receptors in the rat brain
Neuroscience, 1993Co-Authors: David A Morilak, S J Garlow, R D CiaranelloAbstract:Abstract Serotonin 2 Receptors have been implicated in a variety of behavioral and physiological processes, as well as a number of neuropsychiatrie disorders. To specify the brain regions and specific cell types possessing Serotonin 2 Receptors, we conducted an immunocytochemical study of the rat brain using a polyclonal Serotonin 2 Receptor antibody. Perfusion-fixed rat brain sections were processed for immunocytochemistry and reactivity was visualized using an immunoperoxidase reaction. Numerous small, round neurons were heavily labeled in the granular and periglomerular regions of the olfactory bulb. Heavy labeling of medium-sized multipolar and bipolar neurons was also seen in olfactory regions of the ventral forebrain, including the anterior olfactory nucleus and olfactory tubercle. Other regions of the basal forebrain exhibiting high levels of immunoreactivity were the nucleus accumbens, ventral pallidum, Islands of Calleja, fundus striatum and endopyriform nucleus. Immunoreactive neurons were also seen in the lateral amygdala. A dense band of small, round cells was stained in layer 2 of pyriform cortex. In neocortex, a very sparse and even distribution of bipolar and multipolar neurons was seen throughout layers II–VI. A much more faintly labeled population of oval cells was observed in the deep layer of retrosplenial and posterior cingulate cortex, and in the granular layer of somatosensory frontoparietal cortex. A moderate number of medium bipolar and multipolar cells were scattered throughout the neostriatum, and a moderate number of pyramidal and pyramidal-like cells were seen in the CA fields of the hippocampus. Diencephalic areas showing immunolabeling included the medial habenula and anterior pretectal nucleus, with less labeling in the ventral lateral geniculate. In the hindbrain, two dense populations of large multipolar cells were heavily labeled in the pedunculopontine and laterodorsal tegmental nuclei, with lesser labeling in the periaqueductal gray, superior colliculus, spinal trigeminal nucleus and nucleus of the solitary tract. Based on the distribution, localization and morphology of immunoreactive neurons in these regions, we hypothesize that subpopulations of Serotonin 2 containing cells may be GABAergic interneurons or cholinergic neurons. Further, the observed distribution suggests that the physiological effects of Serotonin acting through Serotonin 2 Receptors are mediated by a relatively small number of cells in the brain. These observations may have strong functional implications for the pharmacological treatment of certain neuropsychiatrie disorders.
Youji Hirakawa - One of the best experts on this subject based on the ideXlab platform.
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Dual regulation of L-type Ca2+ channels by Serotonin 2 Receptor stimulation in vascular smooth muscle cells.
American Journal of Physiology-Heart and Circulatory Physiology, 1995Co-Authors: Youji Hirakawa, Takeshi Kuga, Sei Kobayashi, Hideo Kanaide, Akira TakeshitaAbstract:The purpose of the present study was to investigate regulation of voltage-dependent Ca2+ channels by Serotonin in rat aortic smooth muscle cells in primary culture. L- and T-type Ca2+ currents (ICa...
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Dual regulation of L-type Ca2+ channels by Serotonin 2 Receptor stimulation in vascular smooth muscle cells.
The American journal of physiology, 1995Co-Authors: Youji Hirakawa, Takeshi Kuga, Sei Kobayashi, Hideo Kanaide, Akira TakeshitaAbstract:The purpose of the present study was to investigate regulation of voltage-dependent Ca2+ channels by Serotonin in rat aortic smooth muscle cells in primary culture. L- and T-type Ca2+ currents (ICa) were recorded using the whole cell voltage-clamp method. Without pretreatment, in 25 of 30 cells examined, 10 microM Serotonin decreased L-type ICa to various extents (-14 to -72%). However, in the remaining five cells, Serotonin increased L-type ICa 21 +/- 4%. Thus, in 30 cells, Serotonin decreased L-type ICa an average of 22 +/- 5%. In the presence of intracellular heparin (100 micrograms/ml), a blocker of inositol 1,4,5-trisphosphate binding to its Receptor, Serotonin increased L-type ICa in all cells 29 +/- 3% (n = 6). When stored Ca2+ was depleted by pretreatment either with 20 microM ryanodine and 20 mM caffeine or with 100 nM A-23187, Serotonin also increased L-type ICa in all cells 30 +/- 5 (n = 4) or 37 +/- 5% (n = 12), respectively. In the presence of heparin, the Serotonin-induced increase of L-type ICa was prevented by 100 nM staurosporine (2 +/- 3%; n = 6, P < 0.01). The Serotonin-induced decrease of L-type ICa was significantly augmented by 100 nM staurosporine (-43 +/- 10%; n = 5). Phorbol 12,13-dibutylate (PDBu; 1 microM) increased L-type ICa 29 +/- 3% (n = 6), and Serotonin did not further increase L-type ICa after its potentiation by PDBu.(ABSTRACT TRUNCATED AT 250 WORDS)
Paul D Walker - One of the best experts on this subject based on the ideXlab platform.
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Neonatal dopamine depletion reveals a synergistic mechanism of mRNA regulation that is mediated by dopamineD1 and Serotonin2 Receptors and is targeted to tachykinin neurons of the dorsomedial striatum
Neuroscience, 2001Co-Authors: B. M. Campbell, Paul J Gresch, Paul D WalkerAbstract:Abstract It has been hypothesized that dopamine D1 and Serotonin 2 Receptors become sensitized to agonist-mediated regulation of gene expression following loss of dopaminergic innervation to the striatum. We have previously demonstrated that the combined administration of dopamine D1 and Serotonin 2 Receptor agonists to dopamine-depleted adult rats induced preprotachykinin mRNA expression within the periventricular rostral striatum to levels which were significantly different than what could be elicited by either agonist alone. In the present study, we have determined that this phenomenon is revealed only after dopamine depletion. In addition, it is targeted primarily to tachykinin producing neurons of the dorsomedial striatum and is dependent on both dopamine D1 and Serotonin 2 Receptor activation. Preprotachykinin mRNA levels in the intact striatum were unaltered 4 h following an i.p. injection of either SKF-38393 (1 mg/kg, dopamine D1 partial agonist) or (±)-1-(4-Iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI 1 mg/kg, Serotonin 2 agonist). However, the combined application of both agonists increased (+44%) preprotachykinin message levels, but these changes were restricted to the dorsomedial striatum. In adult animals depleted of dopamine as neonates, striatal preprotachykinin mRNA expression was reduced by approximately 50%. From this lowered level of basal expression, DOI or SKF-38393 raised preprotachykinin mRNA levels within the dorsomedial, but not the dorsolateral striatum. Furthermore, co-stimulation of dopamine D1 and Serotonin 2 Receptors produced a nearly four-fold induction of preprotachykinin message levels in the dorsomedial striatum that was significantly greater than either agonist alone. Application of both agonists also elevated preprotachykinin mRNA expression within the dorsolateral striatum, but to a lesser extent. All increases in preprotachykinin mRNA resulting from co-application of SKF-38393 and DOI were prevented by pretreatment with either SCH-23390 (1 mg/kg, dopamine D1 antagonist) or ritanserin (1 mg/kg, Serotonin 2 antagonist). Alternately, preproenkephalin mRNA expression was unaffected by dopamine D1 Receptor stimulation, but was slightly elevated by DOI or both agonists together (42–58%) in intact animals. However, neither agonist treatment in this experiment significantly altered preproenkephalin mRNA expression in the dopamine-depleted striatum which was elevated in response to dopamine lesion alone. Dopamine depletion appears to promote a synergistic interaction between dopamine D1 and Serotonin 2 Receptors that leads to enhanced expression of striatal preprotachykinin mRNA levels. The localization of this phenomenon to tachykinin neurons of the direct striatonigral pathway specifically within the dorsomedial regions of the rostral striatum may be relevant to the problem of dyskinetic behaviors which arise during the pharmacological treatment of movement disorders.
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synergistic interaction between Serotonin 2 Receptor and dopamine d1 Receptor stimulation on striatal preprotachykinin mrna expression in the 6 hydroxydopamine lesioned rat
Molecular Brain Research, 1999Co-Authors: Paul J Gresch, Paul D WalkerAbstract:Abstract The regulation of striatal preprotachykinin (PPT) mRNA expression can be mediated through both dopamine (DA) D1 and Serotonin (5-HT) 5-HT2A/2C Receptors. In the present study, we used in situ hybridization to examine possible synergistic interactions between 5-HT2A/2C and D1 Receptor-mediated regulation of striatal PPT mRNA levels in the rat depleted of DA with 6-hydroxydopamine. Acute administration of the 5-HT2A/2C Receptor agonist DOI (2 mg/kg) significantly increased (+75%) PPT mRNA levels in the dorsal striatum. Acute administration of the D1 Receptor agonist SKF-38393 (2 mg/kg) did not significantly alter PPT mRNA levels in the dorsal striatum. However, the co-administration of SKF-38393 and DOI produced a significant increase (+300%) in striatal PPT mRNA expression restricted to the periventricular region of the dorsal–medial striatum. This synergistic interaction was not observed in the remaining aspect of the dorsal striatum where DOI alone increased PPT mRNA expression. These data show that 5-HT2A/2C and D1 Receptors can act in a synergistic manner to regulate striatal PPT mRNA in a subregion of the DA-depleted striatum.
Herbert Y. Meltzer - One of the best experts on this subject based on the ideXlab platform.
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Effect of Clozapine Treatment on Serotonin-2—Receptor Binding in the Blood Platelets of Schizophrenic Patients
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 1994Co-Authors: Ramesh C. Arora, Herbert Y. MeltzerAbstract:The effect of clozapine and typical neuroleptic drug treatment on platelet Serotonin2 (5-HT2) binding kinetic constants (Kd, Bmax) was studied in schizophrenic patients. Both treatments increased Bmax by a comparable amount, indicating increased numbers of 5-HT2 sites, although not all typical neuroleptic drugs were effective in this regard. Clozapine, but not typical neuroleptic drugs, increased Kd, indicating a lower affinity of the 5-HT2 sites for 5-HT. In a multiple regression model, low Bmax at baseline predicted poor outcome on Brief Psychiatric Rating Scale measures in the clozapine-treated patients but not the neuroleptic-treated patients.
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β-Adrenergic Receptor binding in frontal cortex of suicide victims
Biological psychiatry, 1991Co-Authors: Craig A. Stockmeier, Herbert Y. MeltzerAbstract:The high-affinity binding of the beta-adrenergic Receptor antagonist, [3H]dihydroalprenolol, was measured in homogenates of frontal cortex (Brodmann's areas 8 and 9) of suicide victims and matched controls. Suicides were classified as violent if gunshot, hanging, or jumping was the cause of death and as nonviolent if carbon monoxide poisoning or drug overdose was the cause of death. No significant difference were found between controls and nonviolent or violent suicide victims with regard to the number of beta-adrenergic Receptors (Bmax), or the binding affinity (Kd) of the Receptor. Beta-Adrenergic Receptor binding was not significantly affected by sex, age, race, or postmortem interval. Serotonin-2 Receptor binding (Bmax) in homogenates from the same tissue specimens was previously reported to be significantly increased in violent suicides (Arora and Meltzer 1989). In these sample groups, suicide by violent means appears to be associated with an increase in the number of Serotonin-2, but not beta-adrenergic, Receptors in frontal cortex.
