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No description available.

Thesis (Ph.D.)--Baylor University, 2008. / Includes bibliographical references (p. 113-134).

Proefschrift Universiteit Maastricht. / Auteursnaam op omslag: John C.M. Dumoulin. Met lit. opg., bibliogr. - Met samenvatting in het Nederlands.

We investigated whether chronic administration of guanidinoethane sulfonate, an inhibitor of taurine uptake, could modify the antiepileptic actions of phenobarbital and phenytoin on maximal electroshock seizures in mice. Treatment with 1% guanidinoethane sulfonate decreased the taurine concentration in the brain to 76% of the control value. Under these conditions, neither the severity of tonic convulsions of maximal electroshock seizures nor the threshold for tonic extension caused by electroshock was altered. However, treatment with guanidinoethane sulfonate lessened the antiepileptic actions of phenobarbital and phenytoin on electroshock seizures. The brain concentrations of phenobarbital and phenytoin were unaltered by administration of guanidinoethane sulfonate. The brain concentrations of guanidinoethane sulfonate and total guanidino compounds were unchanged by the injection of either phenobarbital or phenytoin. It is suggested that the observed loss of anticonvulsive potency of phenobarbital and phenytoin may have been related to the decrease in taurine concentration produced by guanidinoethane sulfonate.

Taurine is the second most abundant amino acid in the CNS after glutamate and its functions have been found largely related to intracellular calcium ([Ca2+]i) modulation, osmoregulation, membrane stabilization, reproduction and immunity. The action of taurine has also been implicated in neurotransmission and neuromodulation though its specific sites of action are not fully understood. Isolated retinal neurons from the larval tiger salamanders (Ambystoma tigrinum) were used as a model to study the neuromodulatory role of taurine in the CNS and to gain insights into its potential sites of action. A combination of techniques was used, including whole-cell patch clamp recording to study taurine's regulation of voltage-gated potassium (K+) and Ca2+ channels and Fluo-4AM Ca2+-imaging to study taurine's regulation of glutamate-induced [Ca2+] I,. Taurine was shown to suppress of glutamate-induced [Ca2+] l, in a dose dependent manner. This suppression was mostly sensitive to the glycine rece ptor antagonist Strychnine but insensitive to any GABA receptor antagonist. The remaining strychnine-insensitive effect was inhibited with the protein kinase A (PKA) inhibitor, PKI, suggesting that there was an additional metabotropic pathway. Moreover, using the protein kinase C (PKC) inhibitor, GF109203X, there was an enhancement in strychnine-insensitive taurine's regulation. Taurine inhibits voltage-gated Ca2+ channels in the retinal neurons and has a dual effect on voltage-gated K+ channels. Taurine causes an increase in K+ current amplitude which is further enhanced with PKI and blocked with GF109203X, suggesting that it is through a PKC-dependent pathway negatively controlled by PKA-dependent pathway. / There is a suppression of K+ current by taurine with intracellular application of GF109203X, suggesting that the reduction is through a PKA-dependent pathway. With both PKC and PKA inhibitors there is no longer an enhancement in maximum amplitude but a shift of volt dependence on a hyperpolarizing direction. Taurine's enhancement of K+ current is blocked by the Kv1.3 subtype antagonist Margatoxin, with Kv1.3 accounting for the majority of delayed-rectifier sustained current in bipolar and amacrine cells, as well as 50% of ganglion cells. Interestingly, the enhancement of K+ current by taurine is blocked by 5HT2A antagonist MDL11939, suggesting that activation of PKC is through this metabotropic serotonin receptor subtype. The suppression of voltage-gated Ca2+ channels is reversed with a combination of MDL11939 and the 5HT1A antagonist NAN-190. These results provide the evidence that the natural effect of taurine in the retinal neurons might be dependent on the activation of both 5HT1A and 5HT2A receptors. The high apparent activity of taurine on 5HT receptors could have important implication for the actions of taurine in central brain in which taurine has been known to be beneficial for improving mental health, as well as learning and memory processes. / by Simon Bulley. / Thesis (Ph.D.)--Florida Atlantic University, 2010. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2010. Mode of access: World Wide Web.

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The glycine receptor (GlyR) is a ligand-gated ion channel and member of the nicotinic acetylcholine receptor superfamily. Glycine and the partial agonist taurine are both believed to be the endogenous ligands of the receptor. Partial agonists have lower efficacies than full agonists, eliciting submaximal responses even at saturating concentrations. Recent evidence suggests that efficacy at these receptors is determined by conformational changes that occur early in the process of receptor activation. We previously identified a mutation of the aspartate-97 residue to arginine (D97R), which produces a spontaneously active mutant with behavior that mimics the effects of saturating glycine concentrations on wildtype (WT) GlyR. This D97 residue is hypothesized to form an electrostatic interaction with arginine-119 on an adjacent subunit to stabilize a closed channel closed state. We found that the disruption of this bond converts taurine into a full agonist and greatly increases the efficacies of other [beta]-amino acid partial agonists. Our findings suggest that the determination of efficacy in the GlyR involves the disruption of an inter-subunit electrostatic interaction soon after binding. We next investigated whether the taurine efficacy could be enhanced by ethanol, a well-studied positive allosteric modulator of receptor function. Whole-cell recordings of WT GlyRs demonstrated that alcohol could potentiate the effect of low concentrations of taurine, but did not increase the efficacy of a saturating concentration. Therefore we sought to understand the mechanism by which alcohol enhances the GlyR, because ethanol's actions at inhibitory receptors in the brain are thought to produce many of the physiological effects associated with its use. We examined the effects of 3 [mu]M glycine ± 50 or 200 mM ethanol on outside-out patches expressing WT [alpha]1 GlyR, to determine the effects of alcohol at the single-channel level. Alcohol enhanced GlyR function in a very specific manner. It had minimal effects on open and closed dwell times. Instead, ethanol potentiated GlyR function almost exclusively by increasing burst durations and increasing the number of channel openings per burst, without affecting the percentage of open time within bursts. Kinetic modeling suggests that ethanol increases burst durations by decreasing the rate of glycine unbinding. / text

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