Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of...
Patent
1995-04-21
1998-06-02
Allen, Marianne P.
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
536 235, 4353201, 4352523, C12N 1512
Patent
active
057598541
DESCRIPTION:
BRIEF SUMMARY
This invention relates to newly identified polynucleotides, polypeptides encoded by such polynucleotides, the use of such polynucleotides and polypeptides, as well as the production of such polynucleotides and polypeptides. More particularly, the polypeptide of the present invention is a neurotransmitter transporter and the polypeptide of the present invention is herein sometime referred to as "NTT". The invention also relates to inhibiting the action of such polypeptides.
An essential property of synaptic transmission is the rapid termination of action following neurotransmitter release. For many neurotransmitters, including catecholamines, serotonin, and certain amino acids (e.g., .gamma.-aminobutyric acid (GABA), glutamate, and glycine), rapid termination of synaptic action is achieved by the uptake of the transmitter into the presynaptic terminal and surrounding glial cells by neurotransmitter transporters (Bennett, et al., Life Sci. 15:1045-1056 (1974)). Inhibition or stimulation of neurotransmitter uptake provides a means for modulating the strength of the synaptic action by regulating the available levels of endogenous transmitters. Neurotransmitter transporters are membrane-bound polypeptides which uptake neurotransmitters into the pre-synaptic neuron after the neurotransmitters have crossed the synaptic cleft and acted upon the post-synaptic neuron. Neurotransmitters can be excitatory, such as glutamate, or inhibitory such as GABA.
Affinity neurotransmitter transport is thought to terminate the overall process of synaptic transmission (Iversen, L. L., Br. J. Pharmacol. 41:571-591 (1971)). Recently, cDNAs encoding more than ten different neurotransmitter transporters have been cloned and sequenced. The family of these genes could be divided into three subfamilies, including the GABA and taurine transporters (Liu, Q. R., et al., Proc. Natl. Acad. Sci. USA (in press), (1992)), the amino acid (glycine and proline) transporters (Fremeau, Jr., R. T., et al., Neuron, 8:915-926 (1992)), and the catecholamine transporters (Pacholczyk, T., et al., Nature, 350:350-354 (1991)). The general structure of all these gene products is very similar. They contain twelve potential transmembrane helices and an extended external loop with 3-4 glycosylation sites between membrane segments 3 and 4. The calculated molecular weights of the transporters is about 70 kDa and both their C- and N-terminal peripheral peptides contain about 40 amino acids and may be located on the cytoplasmic side of the membrane. In GABA and catecholamine transporter subfamilies, the amino acid sequence of each member is 60-80% identical to the other members within a subfamily and about 40% identical to members between the two subfamilies (Liu, Q. R., et al., Proc. Natl. Acad. Sci. USA, 89:6639-6643 (1992)). Amino acid transporters, such as the glycine transporter and proline transporter, share about 40-45% homology with all members of the neurotransmitter transporter superfamily. Sequence homology among the members of the neurotransmitter transporter family give clear indication that they evolved from a common ancestral gene. Moreover, partial genomic cloning of several neurotransmitter transporters reveal that in all of them the first intron in the reading frame is located in an identical position (id.).
A GABA.sub.A transporter was the first neurotransmitter system to be cloned and expressed (Guastella, J., et al., Science 249:1303-1306 (1990)) and is one of a family of neurotransmitter transporters cloned within the last year. Recently, a serotonin transporter cDNA has been disclosed in PCT WO 93/08261.
In accordance with one aspect of the present invention, there is provided a novel mature polypeptide which is herein referred to as NTT, as well as fragments, analogs and derivatives thereof. The polypeptide of the present invention is of human origin.
In accordance with another aspect of the present invention, there are provided polynucleotides (DNA or RNA) which encode such polypeptides.
In accordance with yet a further aspect of the present
REFERENCES:
Liu, Q.R. et al., Molecular Characterization of Four Pharmacologically Distinct Alpha-Aminobutyric Acid Transporters in Mouse Brain. J. Biol. Chem., 268:2106-2112 (1993).
Pantanowitz, S. et al., Only One of the Charged Amino Acids Located in the Transmembrane Alpha-Helices of the Gama Aminobutyric Acid Transporter (Subtype A) is Essential For Its Activity, J. Biol. Chem., 268:3222-3225 (1993).
Liu, Q.R. et al., A Rat Brain cDNA Encoding the Neurotransmitter Transporter With an Unusual Structure, FEBS. 315(2):114-118 (1993).
Mestikawy, S.E. et al., Characterization of an Atypical Member of the Na+/C1.sup.- -Dependent Transporter Family: Chromosomal Localization and Distribution in GABAergic and Glutamatergic Neurons in the Rat Brain, Journal of Neurochem., 62:445-455 (1994).
Van Winkle, L.J., Endogenous Amino Acid Transport Systems and Expression of Mammalian Amino Acid Transport Proteins in Xenopus Oocytes, Biochemica Et Biophys. Acta, 1154:157-172 (1993).
Uhl, G.R. and Hartig, P.R., Transporter Explosion: Update on Uptake, Tips, 13:421-425 (1993).
Borden, L.A. et al., Molecular Heterogeneity of the Gamma-Aminobutyric Acid (GABA) Transport System, J.Biol.Chem., 267(69):21098-21104 (1992).
Uhl, G.R. et al., Neurotransmitter Transporter Family cDNAs In a Rat MidBrain Library: `Orphan Transporters` Suggest Sizable Structural Variations, Mol. Brain Res., 16:353-359 (1992).
Clark, J.A. and Amara, S.G., Amino Acid Neurotransmitter Transporters Structure, Function, and Molecular Diversity, BioEssays, 15(5):323-332 (1993).
Fleischmann Robert D.
Li Yi
Allen Marianne P.
Human Genome Sciences Inc.
Mullins J. G.
Olstein Elliot M.
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