Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Primate cell – per se
Patent
1994-12-19
1997-08-19
Walsh, Stephen
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Primate cell, per se
536 235, 435 691, 4352523, 4352551, 4353201, 435325, C12N 119, C12N 121, C12N 1512, C12N 1579
Patent
active
056587864
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Throughout this application various publications are referred to by partial citations within parenthesis. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of these publications, in their entireties, are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
Chemical neurotransmission is a multi-step process which involves release of neurotransmitter from the presynaptic terminal, diffusion across the synaptic cleft, and binding to receptors resulting in an alteration in the electrical properties of the postsynaptic neuron. For most neurotransmitters, transmission is terminated by the rapid uptake of neurotransmitter via specific, high-affinity transporters located in the presynaptic terminal and/or surrounding glial cells (29). Since inhibition of uptake by pharmacologic agents increases the levels of neurotransmitter in the synapse, and thus enhances synaptic transmission, neurotransmitter transporters provide important targets for therapeutic intervention.
The amino acid GABA is the major inhibitory neurotransmitter in the vertebrate central nervous system and is thought to serve as the neurotransmitter at approximately 40% of the synapses in the mammalian brain (13,28). GABAergic transmission is mediated by two classes of GABA receptors. The more prevalent is termed GABA.sub.A, which is a multi-subunit protein containing an intrinsic ligand-gated chloride channel in addition to binding sites for a variety of neuroactive drugs including benzodiazepines and barbiturates (35,73). In contrast, GABA.sub.B receptors couple to G-proteins and thereby activate potassium channels (2,35) and possible alter levels of the second messenger cyclic AMP (35). Positive modulation of GABA.sub.A receptors by diazepam and related benzodiazepines has proven extremely useful in the treatment of generalized anxiety (77) and in certain forms of epilepsy (57).
Inhibition of GABA uptake provides a novel therapeutic approach to enhance inhibitory GABAergic transmission in the central nervous system (36,62). Considerable evidence indicates that GABA can be taken up by both neurons and glial cells, and that the transporters on the two cell types are pharmacologically distinct (15,36,62). A GABA transporter with neuronal-type pharmacology designated GAT-1 has previously been purified and cloned (21), but the molecular properties of other GABA transporters including glial transporter(s) have not yet been elucidated. We now report the cloning of two additional GABA transporters (GAT-2 and GAT-3) with distinct pharmacology and localization, revealing previously unsuspected heterogeneity in GABA transporters.
Taurine (2-aminoethane sulfonic acid) is a sulfur-containing amino acid present in high concentrations in mammalian brain as well as various non-neural tissues. Many functions have been ascribed to taurine in both the nervous system and peripheral tissues. The best understood (and phylogenetically oldest) function of taurine is as an osmoregulator (26,75). Osmoregulation is essential to normal brain function and may also play a critical role in various pathophysiological states such as epilepsy, migraine, and ischemia. The primary mechanism by which neurons and glial cells regulate osmolarity is via the selective accumulation and release of taurine. Taurine influx is mediated via specific, high-affinity transporters which may contribute to efflux as well. Since taurine is slowly degraded, transport is an important means of regulating extracellular taurine levels.
Taurine is structurally related to the inhibitory amino acid .gamma.-aminobutyric acid (GABA) and exerts inhibitory effects on the brain, suggesting a role as a neurotransmitter or neuromodulator. Taurine can be released from both neurons and glial cells by receptor-mediated mechanisms as well as in response to cell volume changes (64). Its effects in the CNS may be mediated by
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Borden Laurence A.
Hartig Paul R.
Smith Kelli E.
Weinshank Richard L.
Kaufman Claire
Synaptic Pharmaceutical Corporation
Walsh Stephen
White John P.
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