Free choline and choline metabolites in rat brain and body fluids: sensitive determination and implications for choline supply to the brain

Klein, Jochen; G, Ricardo Espinoza; Köppen, Andrea; Löffelholz, K.

doi:10.1016/0197-0186(93)90058-d

Cited by 109 publications

(78 citation statements)

References 33 publications

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“…The basal concentration of choline in the cerebrospinal fluid is 7 mM Ž . Klein et al, 1993 , and therefore it is conceivable that during cholinergic neurotransmission local choline concentrations will be higher than the threshold concentration for the potentiating effect of choline.…”

Section: Discussionmentioning

confidence: 99%

Potentiation and inhibition of neuronal α4β4 nicotinic acetylcholine receptors by choline

Zwart

Vijverberg

2000

European Journal of Pharmacology

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The effects of choline on a4b4 nicotinic acetylcholine receptors, expressed in Xenopus oocytes, were investigated using the two-microelectrode voltage clamp technique. Particular attention was paid to the interaction between the effects of acetylcholine and choline. Choline was a low-affinity agonist of a4b4 receptors with an efficacy of 10% as compared to acetylcholine. Responses evoked by 1 mM acetylcholine were potentiated by low concentrations of choline and inhibited by ) 10 mM choline, resulting in a bell-shaped concentration-effect relationship. Conversely, the effects of choline on responses evoked by 300 mM acetylcholine resulted in a monophasic inhibition curve with an IC of 0.87 mM. The data were fitted by a two-site receptor occupation model, which accounts for 50 similar effects of various cholinergic ligands on heteromeric nicotinic receptors. The results indicate that the potentiation was a competitive effect, whereas the inhibition was due to a mixture of competitive and non-competitive effects. It is concluded that choline acts as a potent, endogenous co-agonist at heteromeric a4b4 nicotinic receptors. q

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Section: Discussionmentioning

confidence: 99%

Potentiation and inhibition of neuronal α4β4 nicotinic acetylcholine receptors by choline

Zwart

Vijverberg

2000

European Journal of Pharmacology

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“…The mutated receptor also is activated to 20% of maximal values by choline at a concentration (Ϸ10 M) that is detected in plasma and cerebrospinal fluid (Fig. 1C) (23). We also noted increased 8-(diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride (500 nM, nine oocytes) blockable leakage currents in some oocytes expressing the ␣4L9ЈS͞␤2 receptor (24), and this may arise from constitutive activation of 1-2% of the receptors; that is, channels open even in the absence of agonist (25).…”

Section: Physiological Design and Recombinant Generation Of Mutant Geno-mentioning

confidence: 99%

Point mutant mice with hypersensitive α4 nicotinic receptors show dopaminergic deficits and increased anxiety

Labarca

Schwarz

Deshpande

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

175

170

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Knock-in mice were generated that harbored a leucine-to-serine mutation in the ␣4 nicotinic receptor near the gate in the channel pore. Mice with intact expression of this hypersensitive receptor display dominant neonatal lethality. These mice have a severe deficit of dopaminergic neurons in the substantia nigra, possibly because the hypersensitive receptors are continuously activated by normal extracellular choline concentrations. A strain that retains the neo selection cassette in an intron has reduced expression of the hypersensitive receptor and is viable and fertile. The viable mice display increased anxiety, poor motor learning, excessive ambulation that is eliminated by very low levels of nicotine, and a reduction of nigrostriatal dopaminergic function upon aging. These knock-in mice provide useful insights into the pathophysiology of sustained nicotinic receptor activation and may provide a model for Parkinson's disease.T he mechanism leading from nicotine intake to addiction is not known in detail, but it begins with the activation of neuronal nicotinic acetylcholine receptors (nAChRs). Nicotine elicits dopamine release in several regions of the brain, presumably leading to the reward, motor, and addictive effects (1, 2). The highest-affinity and most abundant nicotine binding in the brain corresponds to the ␣4␤2 nAChR (3). The ␣4 subunit is the principal partner for the ␤2 subunit in brain; ␤2-containing receptors play an important role in nicotine self-administration, in nicotine-stimulated electrophysiological responses in midbrain neurons, and in nicotine-stimulated dopamine release in the ventral striatum (4, 5). The ␣4 subunit and tyrosine hydroxylase are colocalized in dopaminergic neurons (6). Epidemiological studies show that smokers have a lower incidence of Parkinson's disease (7,8), suggesting a protective effect of nicotine via modulation of the dopaminergic system. Both ␣4 and ␤2 knockout mice show only subtle alterations in their physiology or behavior until they reach old age (4, 9, 10). We have used a complementary strategy to understand the roles of ␣4-containing nAChRs. We reasoned that gain of function mutations might generate more noticeable phenotypes, and that these phenotypes would gain relevance from the fact that nicotine and some candidate analgesics (11) are agonists. We have generated lines of knock-in mice by introducing a point mutation into the M2 transmembrane region of the ␣4 subunit to produce a hypersensitive receptor. Materials and MethodsXenopus Oocyte Injections and Electrophysiology. The ␣4 and ␤2 subunits were subcloned into pAMV-PA (12). Capped mRNA transcripts were prepared, and ␣4͞␤2 (2 ng, 1:1) or ␣4L9ЈS͞␤2 (0.2-0.5 ng, 1:1) were microinjected into Xenopus oocytes (12). Twenty-four to seventy-two hours later, two-electrode voltage clamp recordings (12) were made in solutions containing zero Ca 2ϩ .Knock-in Mouse Construction. A 129͞SvJ ␣4 genomic clone containing exon 5 and the L9ЈS mutation was inserted into pKO Scrambler V907 (Lexicon-Genetics, The Woodland...

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“…Like CK, ChAT has a very low affinity for its choline substrate [25,26]. The Km's of these enzymes in brain (which, of course, describe the choline concentrations at which the enzymes operate at only half-maximal velocity) are reportedly 2.6 mM [14] and 540 μM [27], respectively, whereas brain choline levels are only about 30-60 μM [15][16][17]. Hence, the syntheses of both phosphocholine and ACh are highly responsive to treatments which raise or lower brain choline levels.…”

Section: Choline Kinasementioning

confidence: 99%

“…Thus, choline administration increases brain phosphocholine levels in rats [12] and humans [13], because CK's Km for choline (2.6 mM [14]) is much higher than usual brain choline levels (30-60 μM) [15][16][17]. Most commonly the second, CT-catalyzed reaction is most ratelimiting in PC synthesis, either because not all of the CT enzyme is fully activated by being attached to a cellular membrane [18] or because local CTP concentrations are insufficient to saturate the CT [17].…”

Section: Introductionmentioning

confidence: 99%

Oral administration of circulating precursors for membrane phosphatides can promote the synthesis of new brain synapses

Cansev

Wurtman

Sakamoto

et al. 2007

Alzheimer's & Dementia

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Although cognitive performance in humans and experimental animals can be improved by administering the omega-3 fatty acid docosahexaenoic acid (DHA), the neurochemical mechanisms underlying this effect remain uncertain. In general, nutrients or drugs that modify brain function or behavior do so by affecting synaptic transmission, usually by changing the quantities of particular neurotransmitters present within synaptic clefts or by acting directly on neurotransmitter receptors or signal-transduction molecules. We find that DHA also affects synaptic transmission in mammalian brain: Brain cells of gerbils or rats receiving this fatty acid manifest increased levels of phosphatides and of specific pre-or post-synaptic proteins. They also exhibit increased numbers of dendritic spines on postsynaptic neurons. These actions are markedly enhanced in animals that have also received the other two circulating precursors for phosphatidylcholine -uridine (which gives rise to brain UTP and CTP), and choline (which gives rise to phosphocholine). The actions of DHA are reproduced by eicosapentaenoic acid (EPA), another omega-3 compound, but not by the omega-6 fatty acid arachidonic acid (AA). Administration of circulating phosphatide precursors can also increase neurotransmitter release (acetylcholine; dopamine) and affect animal behavior. Conceivably, this treatment might have use in patients with the synaptic loss that characterizes Alzheimer's disease or other neurodegenerative diseases, or occurs after stroke or brain injury.

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Free choline and choline metabolites in rat brain and body fluids: sensitive determination and implications for choline supply to the brain

Cited by 109 publications

References 33 publications

Potentiation and inhibition of neuronal α4β4 nicotinic acetylcholine receptors by choline

Potentiation and inhibition of neuronal α4β4 nicotinic acetylcholine receptors by choline

Point mutant mice with hypersensitive α4 nicotinic receptors show dopaminergic deficits and increased anxiety

Oral administration of circulating precursors for membrane phosphatides can promote the synthesis of new brain synapses

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