hemicholinium 3

Summary

Summary: A potent inhibitor of the high affinity uptake system for CHOLINE. It has less effect on the low affinity uptake system. Since choline is one of the components of ACETYLCHOLINE, treatment with hemicholinium can deplete acetylcholine from cholinergic terminals. Hemicholinium 3 is commonly used as a research tool in animal and in vitro experiments.

Top Publications

  1. Ferguson S, Bazalakova M, Savchenko V, Tapia J, Wright J, Blakely R. Lethal impairment of cholinergic neurotransmission in hemicholinium-3-sensitive choline transporter knockout mice. Proc Natl Acad Sci U S A. 2004;101:8762-7 pubmed
    ..Our results demonstrate that CHT is an essential and regulated presynaptic component of cholinergic signaling and indicate that CHT warrants consideration as a candidate gene for disorders characterized by cholinergic hypofunction...
  2. Apparsundaram S, Ferguson S, George A, Blakely R. Molecular cloning of a human, hemicholinium-3-sensitive choline transporter. Biochem Biophys Res Commun. 2000;276:862-7 pubmed
    ..These studies elucidate the primary structure and chromosomal localization of hCHT and provide a basis for mechanistic analysis of HACU regulation and an investigation of the role of hCHT in disease states...
  3. Klein J, Weichel O, Ruhr J, Dvorak C, Löffelholz K. A homeostatic mechanism counteracting K(+) -evoked choline release in adult brain. J Neurochem. 2002;80:843-9 pubmed
    ..In adult rat brain, this elevation of Ch is counteracted by a homeostatic mechanism such as uptake into brain cells...
  4. Beer A, Slotkin T, Seidler F, Aldridge J, Yanai J. Nicotine therapy in adulthood reverses the synaptic and behavioral deficits elicited by prenatal exposure to phenobarbital. Neuropsychopharmacology. 2005;30:156-65 pubmed
    ..Nicotine administration thus offers a potential therapy for reversing neurobehavioral deficits originating in septohippocampal cholinergic defects elicited by prenatal drug or toxicant exposures...
  5. Campos J, Nunez M, Conejo Garcia A, Sanchez Martin R, Hernandez Alcoceba R, Rodriguez Gonzalez A, et al. QSAR-derived choline kinase inhibitors: how rational can antiproliferative drug design be?. Curr Med Chem. 2003;10:1095-112 pubmed
    ..These results indicate that ChoK can be used as a general target for anticancer drug design against Ras-dependent tumourigenesis...
  6. Qiao D, Seidler F, Abreu Villaca Y, Tate C, Cousins M, Slotkin T. Chlorpyrifos exposure during neurulation: cholinergic synaptic dysfunction and cellular alterations in brain regions at adolescence and adulthood. Brain Res Dev Brain Res. 2004;148:43-52 pubmed
  7. Slotkin T, Ryde I, Seidler F. Separate or sequential exposure to nicotine prenatally and in adulthood: persistent effects on acetylcholine systems in rat brain regions. Brain Res Bull. 2007;74:91-103 pubmed
    ..These effects may contribute to lifelong vulnerability to readdiction...
  8. Slotkin T, Cousins M, Tate C, Seidler F. Persistent cholinergic presynaptic deficits after neonatal chlorpyrifos exposure. Brain Res. 2001;902:229-43 pubmed
    ..The effects are likely to contribute to gender-selective alterations in behavioral performance that persist or emerge long after the termination of exposure and well after the restoration of cholinesterase activity...
  9. Bazalakova M, Wright J, Schneble E, McDonald M, Heilman C, Levey A, et al. Deficits in acetylcholine homeostasis, receptors and behaviors in choline transporter heterozygous mice. Genes Brain Behav. 2007;6:411-24 pubmed
    ..Our studies suggest that CHT hemizygosity results in adequate baseline ACh stores, sufficient to sustain many phenotypes, but normal sensitivities to physical and/or pharmacological challenge require full cholinergic signaling capacity...

More Information

Publications62

  1. Wu H, Chang C, Cheng K, Chang C, Yeh C, Cheng J. Increase of plasma insulin by racecadotril, an inhibitor of enkephalinase, in Wistar rats. Horm Metab Res. 2010;42:261-7 pubmed publisher
    ..Our results suggested that racecadotril increased insulin secretion to lower blood glucose mainly via regulation of parasympathetic tone in Wistar rats...
  2. Ribeiro F, Alves Silva J, Volknandt W, Martins Silva C, Mahmud H, Wilhelm A, et al. The hemicholinium-3 sensitive high affinity choline transporter is internalized by clathrin-mediated endocytosis and is present in endosomes and synaptic vesicles. J Neurochem. 2003;87:136-46 pubmed
    ..We propose that intracellular CHT1 can be recruited during stimulation to increase choline uptake in nerve terminals...
  3. Sigle J, Zander J, Ehret A, Honegger J, Jackisch R, Feuerstein T. High potassium-induced activation of choline-acetyltransferase in human neocortex: implications and species differences. Brain Res Bull. 2003;60:255-62 pubmed
    ..This increase of ChAT activity supports a cholinergic degeneration hypothesis which has been entitled "autocannibalism" by Wurtman [TINS 15 (1992) 177]...
  4. Gahring L, Vasquez Opazo G, Rogers S. Choline promotes nicotinic receptor alpha4 + beta2 up-regulation. J Biol Chem. 2010;285:19793-801 pubmed publisher
    ..These findings extend the view that up-regulation of alpha4 + beta2 nAChRs is a normal physiological response to altered metabolic and inflammatory conditions...
  5. Ohjimi H, Kushiku K, Yamada H, Kuwahara T, Kohno Y, Furukawa T. Increase of acetylcholine release by nebracetam in dog cardiac sympathetic ganglion. J Pharmacol Exp Ther. 1994;268:396-402 pubmed
  6. Payette D, Xie J, Guo Q. Reduction in CHT1-mediated choline uptake in primary neurons from presenilin-1 M146V mutant knock-in mice. Brain Res. 2007;1135:12-21 pubmed
    ..Since human neocortex has recently been shown to possess intrinsic cholinergic innervation, our results indicate that alterations in CHT1-mediated high affinity choline uptake in cortical neurons may contribute to Alzheimer's dementia...
  7. Ferguson S, Blakely R. The choline transporter resurfaces: new roles for synaptic vesicles?. Mol Interv. 2004;4:22-37 pubmed
  8. Mishima K, Tsukikawa H, Inada K, Fujii M, Iwasaki K, Matsumoto Y, et al. Ameliorative effect of vasopressin-(4-9) through vasopressin V(1A) receptor on scopolamine-induced impairments of rat spatial memory in the eight-arm radial maze. Eur J Pharmacol. 2001;427:43-52 pubmed
    ..The activation of these processes by vasopressin-(4-9) is critically involved in the positive effect of vasopressin-(4-9) on scopolamine-induced impairment of spatial memory...
  9. Fujii T, Okuda T, Haga T, Kawashima K. Detection of the high-affinity choline transporter in the MOLT-3 human leukemic T-cell line. Life Sci. 2003;72:2131-4 pubmed
    ..These results suggest that CHT1 plays a role in mediating choline uptake in T-lymphocytes and provides further evidence for the presence of an independent lymphocytic cholinergic system...
  10. Kawada T, Yamazaki T, Akiyama T, Shishido T, Inagaki M, Uemura K, et al. In vivo assessment of acetylcholine-releasing function at cardiac vagal nerve terminals. Am J Physiol Heart Circ Physiol. 2001;281:H139-45 pubmed
    ..We conclude that ACh concentration measured by cardiac microdialysis provides information regarding ACh release and disposition under a variety of pathophysiological conditions in vivo...
  11. Nakamura S, Murayama N, Noshita T, Annoura H, Ohno T. Progressive brain dysfunction following intracerebroventricular infusion of beta(1-42)-amyloid peptide. Brain Res. 2001;912:128-36 pubmed
  12. Kouji H, Inazu M, Yamada T, Tajima H, Aoki T, Matsumiya T. Molecular and functional characterization of choline transporter in human colon carcinoma HT-29 cells. Arch Biochem Biophys. 2009;483:90-8 pubmed publisher
    ..Identification of this novel CTL1-mediated choline uptake system provides a potential new target for therapeutic intervention...
  13. Hong B, Allali Hassani A, Tempel W, Finerty P, MacKenzie F, Dimov S, et al. Crystal structures of human choline kinase isoforms in complex with hemicholinium-3: single amino acid near the active site influences inhibitor sensitivity. J Biol Chem. 2010;285:16330-40 pubmed publisher
  14. Pohorecki R, Head R, Domino E. Effects of selected muscarinic cholinergic antagonists on [3H]acetylcholine release from rat hippocampal slices. J Pharmacol Exp Ther. 1988;244:213-7 pubmed
    ..However, the order of promoting maximal release of [3H]ACh was atropine greater than dexetimide greater than methylatropine greater than aprophen greater than benactyzine greater than pirenzepine...
  15. O Regan S. Binding of [3H]hemicholinium-3 to the high-affinity choline transporter in electric organ synaptosomal membranes. J Neurochem. 1988;51:1682-8 pubmed
  16. Chavez J, Vargas M, Cruz Valderrama J, Montaño L. Non-quantal release of acetylcholine in guinea-pig airways: role of choline transporter. Exp Physiol. 2011;96:460-7 pubmed publisher
    ..We concluded that a Ca(2+)-dependent NQR of ACh is present in cholinergic nerves from guinea-pig airways, and that ChT is involved in this phenomenon...
  17. Zheng Q, Gao M, Mock B, Wang S, Hara T, Nazih R, et al. Synthesis and biodistribution of new radiolabeled high-affinity choline transporter inhibitors [11C]hemicholinium-3 and [18F]hemicholinium-3. Bioorg Med Chem Lett. 2007;17:2220-4 pubmed
    ..The preliminary evaluation of both tracers through biodistribution studies in 9L-glioma rats has been performed, and the uptakes in the heart and tumor were observed, while very low brain uptake was seen...
  18. Beleslin D, Nedelkovski V. Emesis induced by 4-(m-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium chloride (McN-A-343): evidence for a predominant central muscarinic M1 mediation. Neuropharmacology. 1988;27:949-56 pubmed
    ..It is postulated that the emesis produced by McN-A-343, injected into the cerebral ventricles, is mediated through muscarinic M1 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)..
  19. Ray B, Simon J, Lahiri D. Determination of high-affinity choline uptake (HACU) and choline acetyltransferase (ChAT) activity in the same population of cultured cells. Brain Res. 2009;1297:160-8 pubmed publisher
    ..We believe that these simple methods can be used for neurochemical and drug discovery studies in several models of neurodegenerative disorders including Alzheimer's disease...
  20. Ivy M, Newkirk R, Wang Y, Townsel J. A novel choline cotransporter sequestration compartment in cholinergic neurons revealed by selective endosomal ablation. J Neurochem. 2010;112:1295-304 pubmed publisher
    ..It will be necessary to do further studies to identify the novel sequestration compartment supportive of the ChCoT regulated trafficking...
  21. Slotkin T, Card J, Infante A, Seidler F. Prenatal dexamethasone augments the sex-selective developmental neurotoxicity of chlorpyrifos: implications for vulnerability after pharmacotherapy for preterm labor. Neurotoxicol Teratol. 2013;37:1-12 pubmed publisher
    ..Our findings indicate that prior dexamethasone exposure could create a subpopulation that is especially vulnerable to the adverse effects of organophosphates or other developmental neurotoxicants...
  22. Schiaffino Ortega S, Lopez Cara L, Ríos Marco P, Carrasco Jimenez M, Gallo M, Espinosa A, et al. New non-symmetrical choline kinase inhibitors. Bioorg Med Chem. 2013;21:7146-54 pubmed publisher
    ..The analysis of the biological data observed in the described series of compounds mays represents a platform for the design of more active molecules. ..
  23. Chiou G, Li B. Prevention of organophosphate intoxication with presynaptic cholinergic blockers. Life Sci. 1994;55:69-75 pubmed
    ..In all cases, DFP caused cardiovascular suppression before neuromuscular blockade indicating that the cardiovascular system is much more sensitive than the neuromuscular junction to DFP intoxication...
  24. Fujii T, Masai M, Misawa H, Okuda T, Takada Takatori Y, Moriwaki Y, et al. Acetylcholine synthesis and release in NIH3T3 cells coexpressing the high-affinity choline transporter and choline acetyltransferase. J Neurosci Res. 2009;87:3024-32 pubmed publisher
  25. Bevan C, Kinne R. Choline transport in collecting duct cells isolated from the rat renal inner medulla. Pflugers Arch. 1990;417:324-8 pubmed
    ..Furthermore, the increase in the GPC content under hyperosmotic conditions is not associated with increased activity of the transport systems of biosynthetic precursors...
  26. Müller S, Holzapfel K, Seidl C, Treiber U, Krause B, Senekowitsch Schmidtke R. Characterization of choline uptake in prostate cancer cells following bicalutamide and docetaxel treatment. Eur J Nucl Med Mol Imaging. 2009;36:1434-42 pubmed publisher
    ..Since little is known about uptake mechanisms, the aim of this study was to characterize choline uptake in prostate cancer cells, also following anti-androgen treatment or chemotherapy...
  27. Bertolini A, Ferrari W, Guarini S. Adrenocorticotropic hormone (ACTH) and centrally-acting cholinomimetic drugs improve survival of rats with severe hemorrhagic shock through distinct central cholinergic mechanisms. Resuscitation. 1989;18:289-97 pubmed
    ..That ACTH and cholinergic drugs activate different central cholinergic mechanisms is also suggested by the fact that cholinergic drugs have a centrally-mediated hypertensive action in normal animals, which is not shared by ACTH...
  28. Slotkin T, Ryde I, Seidler F. Additive and synergistic effects of fetal nicotine and dexamethasone exposure on cholinergic synaptic function in adolescence and adulthood: Implications for the adverse consequences of maternal smoking and pharmacotherapy of preterm delivery. Brain Res Bull. 2010;81:552-60 pubmed publisher
    ..Our results thus point to potentially worse neurobehavioral outcomes of the pharmacotherapy of preterm labor in the offspring of smokers...
  29. Poulain B, Fossier P, Baux G, Tauc L. Hemicholinium-3 facilitates the release of acetylcholine by acting on presynaptic nicotinic receptors at a central synapse in Aplysia. Brain Res. 1987;435:63-70 pubmed
    ..The possible blockage of muscarinic presynaptic receptors by HC-3 was also considered. Hemicholinium-15 was without effect on ACh release but was nevertheless able to prevent the presynaptic action of HC-3...
  30. Takano M, Katsura T, Tomita Y, Yasuhara M, Hori R. Transport mechanism of choline in rat renal brush-border membrane. Biol Pharm Bull. 1993;16:889-94 pubmed
  31. Kristofikova Z, Platilová V, Klaschka J. Age- and sex-dependent effects of ethanol on hippocampal hemicholinium-3 sensitive choline carriers during postnatal development of rats. Neurochem Res. 2003;28:397-405 pubmed
    ..The direct effects of ethanol on male choline carriers can contribute to the inhibition of acetylcholine synthesis and to sex-dependent neurotoxic effects of alcohol applied in vivo during early and late postnatal period...
  32. Ebel H, Hollstein M, Gunther T. Role of the choline exchanger in Na(+)-independent Mg(2+) efflux from rat erythrocytes. Biochim Biophys Acta. 2002;1559:135-44 pubmed
    ..Inhibition of choline efflux and of Mg(2+) efflux in choline medium occurred as follows: quinine>cinchonine>HC-3>DoTMA. Mg(2+) efflux was reduced to the same degree by these inhibitors as was the [(14)C]choline efflux...
  33. Boccia M, Blake M, Acosta G, Baratti C. Post-retrieval effects of icv infusions of hemicholinium in mice are dependent on the age of the original memory. Learn Mem. 2006;13:376-81 pubmed
    ..This implies that the vulnerability of a reactivated memory to a specific treatment, as the one used in this study, inversely correlates with the age of the original memory, and it is likely to determine memory reconsolidation processes...
  34. Greensmith L, Ng P, Mohaghegh P, Vrbova G. Reducing transmitter release from nerve terminals influences motoneuron survival in developing rats. Neuroscience. 2000;97:357-62 pubmed
    ..These results indicate that the release of acetylcholine from motor nerve terminals plays an important role in the development and survival of motoneurons...
  35. Yalcin M, Erturk M. The involvement of the central cholinergic system in the pressor and bradycardic effects of centrally administrated melittin in normotensive conscious rats. Neuropeptides. 2007;41:103-10 pubmed
    ..c.v. injection of melittin in the normotensive conscious rats. Moreover, decreased uptake of choline to the cholinergic terminals may consider that melittin activates central choline and acetylcholine release, as well...
  36. Gilissen C, De Groot T, Bronfman F, Van Leuven F, Verbruggen A, Bormans G. Evaluation of 18F-FA-4 and 11C-pipzA-4 as radioligands for the in vivo evaluation of the high-affinity choline uptake system. J Nucl Med. 2003;44:269-75 pubmed
  37. Okuda T, Konishi A, Misawa H, Haga T. Substrate-induced internalization of the high-affinity choline transporter. J Neurosci. 2011;31:14989-97 pubmed publisher
    ..Our results collectively suggest that the internalization of CHT1 is induced by extracellular substrate, providing a novel feedback mechanism for the regulation of acetylcholine synthesis at the cholinergic presynaptic terminals...
  38. Zurkovsky L, Bychkov E, Tsakem E, Siedlecki C, Blakely R, Gurevich E. Cognitive effects of dopamine depletion in the context of diminished acetylcholine signaling capacity in mice. Dis Model Mech. 2013;6:171-83 pubmed publisher
    ..The results suggest that combined loss of DA and ACh could be sufficient for pathogenesis of specific cognitive deficits in PDD...
  39. Buccafusco J, Davis J, Shuster L, Buccafusco C, Gattu M. The importance of brainstem cholinergic neurons in the pressor response to cocaine. J Pharmacol Exp Ther. 2005;312:179-91 pubmed
  40. Rodriguez Gonzalez A, Ramirez de Molina A, Fernandez F, Ramos M, Del Carmen Nunez M, Campos J, et al. Inhibition of choline kinase as a specific cytotoxic strategy in oncogene-transformed cells. Oncogene. 2003;22:8803-12 pubmed
    ..These results indicate that inhibition of ChoK is a rather specific strategy for the cytotoxic treatment of transformed cells...
  41. Ribeiro Carvalho A, Lima C, Filgueiras C, Manhães A, Abreu Villaca Y. Nicotine and ethanol interact during adolescence: effects on the central cholinergic systems. Brain Res. 2008;1232:48-60 pubmed publisher
    ..These results indicate that the central cholinergic system is a site at which nicotine and ethanol interact. This interaction might underlie the association between tobacco and alcohol consumption during adolescence...
  42. Sholl Franco A, Marques P, Paes de Carvalho R, de Araujo E. Antagonistic and synergistic effects of combined treatment with interleukin-2 and interleukin-4 on mixed retinal cell cultures. J Neuroimmunol. 2001;113:40-8 pubmed
    ..5 U ml(-1)). However, high concentrations of IL-2 (50 U ml(-1)) and IL-4 (5 U ml(-1)) elicited an antagonistic effect. Our data indicate an important role for interleukins during retinal development...
  43. Naves L, Van der Kloot W. Repetitive nerve stimulation decreases the acetylcholine content of quanta at the frog neuromuscular junction. J Physiol. 2001;532:637-47 pubmed
    ..We conclude that the inhibitors do not block a significant fraction of the ACh loading into reformed reserve vesicles and propose that ACh can be loaded in a series of steps...
  44. Cavun S, Savci V, Ulus I. Centrally injected CDP-choline increases plasma vasopressin levels by central cholinergic activation. Fundam Clin Pharmacol. 2004;18:71-7 pubmed
    ..In conclusion, intracerebroventricularly injected CDP-choline can increase plasma vasopressin levels by activating central nicotinic cholinergic receptors through the activation of presynaptic cholinergic mechanisms...
  45. Chen S, Pan H. Spinal endogenous acetylcholine contributes to the analgesic effect of systemic morphine in rats. Anesthesiology. 2001;95:525-30 pubmed
    ..In the present study, we explored the functional importance of spinal endogenous acetylcholine in the analgesic action produced by intravenous morphine...
  46. Ali S, Watson M, Osborne R. The stimulant cathartic, emodin, contracts the rat isolated ileum by triggering release of endogenous acetylcholine. Auton Autacoid Pharmacol. 2004;24:103-5 pubmed
    ..These data suggest that, emodin causes contraction of the ileum by triggering the release of endogenous ACh which acts on muscarinic receptors to cause contraction of the rat isolated ileum preparation...
  47. Steffens M, Szabo B, Klar M, Rominger A, Zentner J, Feuerstein T. Modulation of electrically evoked acetylcholine release through cannabinoid CB1 receptors: evidence for an endocannabinoid tone in the human neocortex. Neuroscience. 2003;120:455-65 pubmed
    ..The endocannabinoid tone is high in the human, but not in the mouse neocortex and is dependent on neuronal activity. SR141716 acts as a competitive CB1 receptor antagonist...
  48. Cobb S, Bulters D, Suchak S, Riedel G, Morris R, Davies C. Activation of nicotinic acetylcholine receptors patterns network activity in the rodent hippocampus. J Physiol. 1999;518:131-40 pubmed
    ..5. In summary, ACh-mediated activation of nAChRs tailors the pattern of network activity into theta-frequency depolarizing episodes as opposed to synchronized individual events at much lower frequencies...
  49. Picconi B, Barone I, Pisani A, Nicolai R, Benatti P, Bernardi G, et al. Acetyl-L-carnitine protects striatal neurons against in vitro ischemia: the role of endogenous acetylcholine. Neuropharmacology. 2006;50:917-23 pubmed
    ..These findings show that ALC exert a neuroprotective action against in vitro ischemia. This neuroprotective effect requires the activity of choline uptake system and the activation of M2 muscarinic receptors...
  50. Lee W, Kao S, Liu I, Cheng J. Increase of insulin secretion by ginsenoside Rh2 to lower plasma glucose in Wistar rats. Clin Exp Pharmacol Physiol. 2006;33:27-32 pubmed
    ..ginseng root. Thus, ginsenoside Rh2 may be applied as an adjuvant for the management of diabetes...
  51. Geldenhuys W, Lockman P, Nguyen T, Van der Schyf C, Crooks P, Dwoskin L, et al. 3D-QSAR study of bis-azaaromatic quaternary ammonium analogs at the blood-brain barrier choline transporter. Bioorg Med Chem. 2005;13:4253-61 pubmed
    ..506 and the non-cross-validated r2 was 0.804. This new model was able to better predict BBB-choline transporter affinity of hemicholinium-3 (predicted 65 microM, actual 54 microM), when compared to an earlier model (predicted 316 microM)...
  52. Prado W, Segalla D. Antinociceptive effects of bethanechol or dimethylphenylpiperazinium in models of phasic or incisional pain in rats. Brain Res. 2004;1018:272-82 pubmed
    ..The acetylcholine released by DM in turn induces antinociception via activation of muscarinic receptors...
  53. Muramatsu I, Uwada J, Masuoka T, Yoshiki H, Sada K, Lee K, et al. Regulation of synaptic acetylcholine concentrations by acetylcholine transport in rat striatal cholinergic transmission. J Neurochem. 2017;143:76-86 pubmed publisher
    ..In addition, these data suggest that the recycling of ACh-derived choline may be minor in cholinergic terminals. This study reveals a new mechanism of cholinergic transmission in the central nervous system. ..