Taurine demonstrates multiple cellular functions including a central role as a neurotransmitter, as a trophic factor in CNS development, in maintaining the structural integrity of the membrane, in regulating calcium transport and homeostasis, as an osmolyte, as a neuromodulator and as a neuroprotectant. The neurotransmitter properties of taurine are illustrated by its ability to elicit neuronal hyperpolarization, the presence of specific taurine synthesizing enzyme and receptors in the CNS and the presence of a taurine transporter system. Taurine exerts its neuroprotective functions against the glutamate induced excitotoxicity by reducing the glutamate-induced increase of intracellular calcium level, by shifting the ratio of Bcl-2 and Bad ratio in favor of cell survival and by reducing the ER stress. The presence of metabotropic taurine receptors which are negatively coupled to phospholipase C (PLC) signaling pathway through inhibitory G proteins is proposed, and the evidence supporting this notion is also presented.

In stroke and neurodegenerative disease, neuronal excitotoxicity, caused by increased extracellular glutamate levels, is known to result in calcium overload and mitochondrial dysfunction. Mitochondrial deficits may involve a deficiency in energy supply as well as generation of high levels of oxidants which are key contributors to neuronal cell death through necrotic and apoptotic mechanisms. Excessive glutamate receptor stimulation also results in increased nitric oxide generation which can be detrimental to cells as nitric oxide interacts with superoxide to form the toxic molecule peroxynitrite. High level oxidant production elicits neuronal apoptosis through the actions of proapoptotic Bcl-2 family members resulting in mitochondrial permeability transition pore opening. In addition to apoptotic responses to severe stress, accumulation of misfolded proteins and high levels of oxidants can elicit endoplasmic reticulum (ER) stress pathways which may also contribute to induction of apoptosis. Two categories of therapeutics are discussed that impact major pro-death events that include induction of oxidants, calcium overload, and ER stress. The first category of therapeutic agent includes the amino acid taurine which prevents calcium overload and is also capable of preventing ER stress by inhibiting specific ER stress pathways. The second category involves N-methyl-D-aspartate receptor (NMDA receptor) partial antagonists illustrated by S-Methyl-N, N-diethyldithiocarbamate sulfoxide (DETC-MeSO), and memantine. DETC-MeSO is protective through preventing excitotoxicity and calcium overload and by blocking specific ER stress pathways. Another NMDA receptor partial antagonist is memantine which prevents excessive glutamate excitation but also remarkably allows maintenance of physiological neurotransmission. Targeting of these major sites of neuronal damage using pharmacological agents is discussed in terms of potential therapeutic approaches for neurological disorders.

1 The 5-hydroxytryptamine (5-HT) receptors mediating vasoconstriction in isolated human small muscular pulmonary arteries (SMPAs) were determined using techniques of wire myography and reverse transcription-polymerase chain reaction (RT ± PCR). 2 The agonists 5-HT, 5-carboxamidotryptamine (5-CT, unselective for 5-HT 1 receptors) and sumatriptan (selective for 5-HT 1B/D receptors) all caused contraction and were equipotent (pEC 50 s: 7.0+0.2, 7.1+0.3 and 6.7+0.1, respectively) suggesting the presence of a 5-HT 1 receptor. 3 Ketanserin (5-HT 2A -selective antagonist, 0.1 mM) inhibited 5-HT-induced contractions only at non-physiological/pathological concentrations of 5-HT (40.1 mM) whilst GR55562 (5-HT 1B/1D -selective antagonist, 1 mM) inhibited 5-HT-induced contractions at all concentrations of 5-HT (estimated pK B =7.7+0.2). SB-224289 (5-HT 1B -selective antagonist, 0.2 mM) inhibited sumatriptaninduced contractions (estimated pK B =8.4+0.1) whilst these were una ected by the 5-HT 1D -selective antagonist BRL15572 (0.5 mM) suggesting that the 5-HT 1B receptor mediates vasoconstriction in this vessel. 4 RT ± PCR con®rmed the presence of substantial amounts of mRNA for the 5-HT 2A and 5-HT 1B receptor subtypes in these arteries whilst only trace amounts of 5-HT 1D receptor message were evident. 5 These ®ndings suggest that a heterogeneous population of 5-HT 2A and 5-HT 1B receptors co-exist in human small muscular pulmonary arteries but that the 5-HT 1B receptor mediates 5-HT-induced vasoconstriction at physiological and pathophysiological concentrations of 5-HT. These results have important implications for the treatment of pulmonary hypertension in which the 5-HT 1B receptor may provide a novel and potentially important therapeutic target.

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Redox-sensitive cysteine residues are present in the interaction domains of many protein complexes. There are examples in all of the major categories of transcription factors, including basic region, leucine zipper, helix-loop-helix, and zinc finger. Zinc finger structures require at least two zinc-coordinated cysteine sulfhydryl groups, and oxidation or alkylation of these can eliminate DNA-binding and transcriptional functions. We review here the evidence for oxidation of zinc finger cysteines, the pathways and reactive oxygen intermediates involved, and the functional and physiological consequences of these reactions. Despite skepticism that the strongly reducing intracellular environment would permit significant oxidation of cysteine residues within zinc finger transcription factors, there is compelling evidence that oxidation occurs both in vitro and in vivo. Early reports demonstrating reversible oxidation of zinc-coordinated cysteines with loss of binding function in vitro were shown to reflect accurately the changes in intact cells, and these in turn have been shown to correlate with physiological changes. In particular, the accumulation of oxidized Spl zinc fingers during aging, and estrogen receptors in tamoxifen-resistant breast cancers are dramatic examples of what may be a general sensitivity of zinc finger factors to changes in the redox state of the cell.