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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/12/23 06:16:12」(JST)
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- Functional characterization of rare variants in human dopamine receptor D4 gene by genotype-phenotype correlations.
- Antony Michealraj K1, Jatana N2, Jafurulla M3, Narayanan L2, Chattopadhyay A3, Thelma BK4.Author information 1Department of Genetics, University of Delhi South Campus, New Delhi, India.2Bioinformatics Infrastructure Facility, Sri Venkateswara College, New Delhi, India.3Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Uppal Road, Hyderabad 500 007, India.4Department of Genetics, University of Delhi South Campus, New Delhi, India. Electronic address: thelmabk@gmail.com.AbstractNext generation sequencing technologies have facilitated a notable shift from common disease common variant hypothesis to common disease rare variant, as also witnessed in recent literature on schizophrenia. Dopamine receptor D4 (DRD4), a G-protein coupled receptor is associated with psychiatric disorders and has high affinity for atypical antipsychotic clozapine. We investigated the functional role of rare genetic variants in DRD4 which may have implications for translational medicine. CHO-K1 cells independently expressing four rare non-synonymous variants of DRD4 namely R237L, A281P, S284G, located in third cytosolic loop and V194G, located in fifth transmembrane domain were generated. Their genotype-phenotype correlations were evaluated using [3H]spiperone binding, G-protein activation and molecular dynamics-simulation studies. A281P and S284G were functionally similar to wildtype (WT). With R237L, potency of dopamine and quinpirole reduced ∼ 6-fold and 3-fold respectively compared to WT; [3H]spiperone binding studies showed reduction in total number of binding sites (∼40%) but not binding affinity, in silico docking studies revealed that binding of both dopamine and spiperone to R237L was structurally similar to WT. Of note, V194G variant failed to inhibit forskolin stimulated adenylate cyclase activity and phosphorylate extracellular signal-regulated kinase; showed significant reduction in binding affinity (Kd = 2.16 nM) and total number of binding sites (∼66%) compared to WT in [3H]spiperone binding studies; and ligand docking studies showed that binding of dopamine and spiperone is superficial due to probable structural alteration. Transmembrane variant V194G in DRD4.4 results in functional alteration warranting continuing functional analysis of rare variants.
- Neuroscience.Neuroscience.2014 Jan 6. pii: S0306-4522(13)01092-0. doi: 10.1016/j.neuroscience.2013.12.059. [Epub ahead of print]
- Next generation sequencing technologies have facilitated a notable shift from common disease common variant hypothesis to common disease rare variant, as also witnessed in recent literature on schizophrenia. Dopamine receptor D4 (DRD4), a G-protein coupled receptor is associated with psychiatric dis
- PMID 24406443
- Serotonin contracts the rat mesenteric artery by inhibiting 4-aminopyridine-sensitive Kv channels via the 5-HT2A receptor and Src tyrosine kinase.
- Sung DJ1, Noh HJ2, Kim JG2, Park SW2, Kim B2, Cho H3, Bae YM2.Author information 11] Department of Physiology and the Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea [2] Division of Sport Science, College of Science and Technology, Konkuk University, Choongju, Korea.2Department of Physiology, Institute of Functional Genomics, and Research Institute of Medical Science, Konkuk University School of Medicine, Choongju, Korea.3Department of Physiology and the Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.AbstractSerotonin (5-hydroxytryptamine (5-HT)) is a neurotransmitter that regulates a variety of functions in the nervous, gastrointestinal and cardiovascular systems. Despite such importance, 5-HT signaling pathways are not entirely clear. We demonstrated previously that 4-aminopyridine (4-AP)-sensitive voltage-gated K(+) (Kv) channels determine the resting membrane potential of arterial smooth muscle cells and that the Kv channels are inhibited by 5-HT, which depolarizes the membranes. Therefore, we hypothesized that 5-HT contracts arteries by inhibiting Kv channels. Here we studied 5-HT signaling and the detailed role of Kv currents in rat mesenteric arteries using patch-clamp and isometric tension measurements. Our data showed that inhibiting 4-AP-sensitive Kv channels contracted arterial rings, whereas inhibiting Ca(2+)-activated K(+), inward rectifier K(+) and ATP-sensitive K(+) channels had little effect on arterial contraction, indicating a central role of Kv channels in the regulation of resting arterial tone. 5-HT-induced arterial contraction decreased significantly in the presence of high KCl or the voltage-gated Ca(2+) channel (VGCC) inhibitor nifedipine, indicating that membrane depolarization and the consequent activation of VGCCs mediate the 5-HT-induced vasoconstriction. The effects of 5-HT on Kv currents and arterial contraction were markedly prevented by the 5-HT2A receptor antagonists ketanserin and spiperone. Consistently, α-methyl 5-HT, a 5-HT2 receptor agonist, mimicked the 5-HT action on Kv channels. Pretreatment with a Src tyrosine kinase inhibitor, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, prevented both the 5-HT-mediated vasoconstriction and Kv current inhibition. Our data suggest that 4-AP-sensitive Kv channels are the primary regulator of the resting tone in rat mesenteric arteries. 5-HT constricts the arteries by inhibiting Kv channels via the 5-HT2A receptor and Src tyrosine kinase pathway.
- Experimental & molecular medicine.Exp Mol Med.2013 Dec 13;45:e67. doi: 10.1038/emm.2013.116.
- Serotonin (5-hydroxytryptamine (5-HT)) is a neurotransmitter that regulates a variety of functions in the nervous, gastrointestinal and cardiovascular systems. Despite such importance, 5-HT signaling pathways are not entirely clear. We demonstrated previously that 4-aminopyridine (4-AP)-sensitive vo
- PMID 24336234
- Mechanism of dopamine D2 receptor-induced Ca(2+) release in PC-12 cells.
- Frégeau MO, Carrier M, Guillemette G.Author information Faculty of Medicine and Health sciences, Department of Pharmacology, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4 Canada.AbstractIntracellular Ca(2+) levels are tightly regulated in the neuronal system. The loss of Ca(2+) homeostasis is associated with many neurological diseases and neuropsychiatric disorders such as Parkinson's, Alzheimer's, and schizophrenia. We investigated the mechanisms involved in intracellular Ca(2+) signaling in PC-12 cells. The stimulation of NGF-differentiated PC-12 cells with 3μM ATP caused an early Ca(2+) release followed by a delayed Ca(2+) release. The delayed Ca(2+) release was dependent on prior ATP priming and on dopamine secretion by PC-12 cells. Delayed Ca(2+) release was abolished in the presence of spiperone, suggesting that it is due to the activation of D2 dopamine receptors (D2R) by dopamine secreted by PC-12 cells. This was shown to be independent of PKA activation but dependent on PLC activity. An endocytosis step was required for inducing the delayed Ca(2+) release. Given the importance of calcyon in clathrin-mediated endocytosis, we verified the role of this protein in the delayed Ca(2+) release phenomenon. siRNA targeting of calcyon blocked the delayed Ca(2+) release, decreased ATP-evoked IP3R-mediated Ca(2+) release, and impaired subsequent Ca(2+) oscillations. Our results suggested that calcyon is involved in an unknown mechanism that causes a delayed IP3R-mediated Ca(2+) release in PC-12 cells. In schizophrenia, Ca(2+) dysregulation may depend on the upregulation of calcyon, which maintains elevated Ca(2+) levels as well as dopamine signaling.
- Cellular signalling.Cell Signal.2013 Dec;25(12):2871-7. doi: 10.1016/j.cellsig.2013.08.021. Epub 2013 Sep 19.
- Intracellular Ca(2+) levels are tightly regulated in the neuronal system. The loss of Ca(2+) homeostasis is associated with many neurological diseases and neuropsychiatric disorders such as Parkinson's, Alzheimer's, and schizophrenia. We investigated the mechanisms involved in intracellular Ca(2+) s
- PMID 24055909
Japanese Journal
- Haloperidol, spiperone, pimozide and aripiprazole reduce intracellular dopamine content in PC12 cells and rat mesencephalic cultures: Implication of inhibition of vesicular transport.
- Matsuo Takaaki,Izumi Yasuhiko,Wakita Seiko,Kume Toshiaki,Takada-Takatori Yuki,Sawada Hideyuki,Akaike Akinori
- European journal of pharmacology 640(1-3), 68-74, 2010-08-25
- … Pretreatment with haloperidol, spiperone, pimozide, aripiprazole and risperidone markedly inhibited high potassium-evoked dopamine release. … Haloperidol, spiperone, pimozide, chlorpromazine, aripiprazole and olanzapine evoked dopamine release, while sulpiride and risperidone had no effect. … In addition, haloperidol, spiperone, pimozide, aripiprazole and risperidone reduced intracellular dopamine content in a concentration-dependent manner. …
- NAID 120002426867
- Possible Involvement of Endogenous 5-HT in Aggravation of Cerulein-Induced Acute Pancreatitis in Mice
- , , [他], , , , ,
- Journal of pharmacological sciences 105(3), 240-250, 2007-11-20
- … Selective 5-HT2A antagonists (risperidone, spiperone, ketanserin, AMI-193, and MDL 11,939) dose-dependently attenuated the hyperenzymemia; …
- NAID 10024316598
- Evidence for the Involvement of Dopamine in Ambulation Promoted by Menthol in Mice
- ,
- Journal of pharmacological sciences 91(2), 125-135, 2003-02-01
- … We then examined effects of the DA antagonists chlorpromazine, haloperidol, fluphenazine, spiperone, and SCH12679 on the ability of BUP and ME to promote ambulation. …
- NAID 130000073714
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Related Pictures
![SPIPERONE, [BENZENE RING-3H] | 80154-50-3](https://1mg.info/0/d/d/1223.jpg)
★リンクテーブル★
| リンク元 | 「スピペロン」 |
「スピペロン」
- 英
- spiperone、spiroperidol
- 商
- スピロピタン
- 関
- スピロペリドール、抗精神病薬
- 統合失調症治療薬;ブチロフェノン系