Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Patent
1992-11-30
1999-11-09
Ulm, John
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
435 72, 435 691, 4352523, 4353201, 530350, 436501, 536 235, C07K 14705, C12N 510, C12N 1512
Patent
active
059811935
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to neuronal nicotinic acetylcholine receptor genes and proteins. In a particular aspect, the present invention relates to human neuronal nicotinic acetylcholine receptor genes and proteins. In a further aspect, the present invention relates to methods for determining the presence of neuronal nicotinic acetylcholine receptor activity in cells thought to have genes encoding such proteins. In yet another aspect, the present invention relates to methods for determining the agonist or antagonist activity of compounds which might interact with neuronal nicotinic acetylcholine receptors.
BACKGROUND OF THE INVENTION
Most theories on how the nervous system functions depend heavily on the existence and properties of cell to cell contacts known as synapses. For this reason, the study of synapses has been a focal point for neuroscience research for many decades.
Because of its accessibility to biochemical and electrophysiological techniques, and because of its elegant, well defined structure, the neuromuscular synapse (also known as the neuromuscular junction), which occurs at the point of nerve to muscle contact, is one of the most studied and best understood synapses. At the neuromuscular junction, the nerve cell releases a chemical neurotransmitter, acetylcholine, which binds to nicotinic acetylcholine receptor proteins located on post-synaptic muscle cells. The binding of acetylcholine results in a conformational change in the nicotinic acetylcholine receptor protein. This change is manifested by the opening of a transmembrane channel in the receptor which is permeable to cations. The resulting influx of cations depolarizes the muscle and ultimately leads to muscle contraction.
Biological and structural studies have shown that the nicotinic acetylcholine receptor in muscle is a glycoprotein composed of five subunits with the stoichiometry .alpha..alpha..beta..gamma..DELTA. (alpha-alpha-beta-gamma-delta). From these same studies, it is known that each of the subunits has a mass of about 50-60 kilodaltons and is encoded by a separate gene. In vitro reconstitution experiments have shown that this .alpha..alpha..beta..gamma..DELTA. complex is a functional receptor containing both ligand binding sites and a ligand-gated transmembrane channel.
It is now known that a variety of neurotransmitters and neurotransmitter receptors exist in the central and peripheral nervous systems. Despite this knowledge, there is still little understanding of the diversity of receptors for a particular neurotransmitter, or of how this diversity might generate different responses to a given neurotransmitter, or to other modulating ligands, in different regions of the brain. On a larger scale, there is little appreciation of how the use of a particular synapse makes it more or less efficient, or hnges in neuronal circuits might be accomplished by the modification of synapses.
An understanding of the molecular mechanisms involved in neurotransmission in the central nervous system is limited by the complexity of the system. The cells are small, have extensive processes, and often have thousands of synapses deriving from inputs from many different parts of the brain. In addition, the actual number of neurotransmitter receptors is low, making their purification difficult, even under the best of circumstances. Consequently, neither cellular nor biochemical approaches to studying neurotransmission in the central nervous system has been particularly fruitful. This is unfortunate because it is quite probable that the treatment of dementia, Alzheimer's disease and other forms of mental illness will involve modification of synaptic transmission with specific drugs.
Nicotinic acetylcholine receptors found at the vertebrate neuromuscular junction, in vertebrate sympathetic ganglia and in the vertebrate central nervous system can be distinguished pharmacologically on the basis of ligands that open or block the ion channel. For example, the elapid .alpha.-neurotoxins that block activation of nicotinic acety
REFERENCES:
patent: 4837148 (1989-06-01), Cregg
patent: 4855231 (1989-08-01), Stroman et al.
patent: 4859609 (1989-08-01), Dull et al.
patent: 4882279 (1989-11-01), Cregg
patent: 4929555 (1990-05-01), Cregg et al.
patent: 4981784 (1991-01-01), Evans et al.
patent: 5024939 (1991-06-01), Gorman
patent: 5071773 (1991-12-01), Evans et al.
patent: 5091518 (1992-02-01), Sucov et al.
patent: 5369028 (1994-11-01), Harpold et al.
patent: 5386025 (1995-01-01), Jay et al.
patent: 5401629 (1995-03-01), Harpold et al.
patent: 5436128 (1995-07-01), Harpold et al.
Anand and Lindstrom, "Nucleotide sequence of the human nicotinic acetylcholine receptor .beta.2 subunit gene," Nucleic Acids Research, 18:4272 (1990).
Beeson et al., "The human muscle nicotinic acetylcholine receptor .alpha.-subunit exists as two isoforms: a novel exon," The EMBO Journal 9:2101-2106 (1990).
Boulter et al., "Functional expression of two neuronal nicotinic acetylcholine receptors from cDNA clones identifies a gene family," Proc. Natl. Acad. Sci, USA, 84:7763-7767 (1987).
Boulter et al., "Isolation of a cDNA clone coding for a possible neural nicotine acetylcholine receptor .alpha.-subunit," Nature, 319:368-374 (1986).
Claudio et al., "Genetic Reconstitution of Functional Acetylcholine Receptor Channels in Mouse Fibroblasts," Science 238: 1688-1694 (1987).
Clementi et al., "Pharmacological Characterization of Cholinergic Receptors in a Human Neuroblastoma Cell Line," Journal of Neurochemistry, 47:291-297 (1986).
Conti-Tronconi et al., "Brain and muscle nicotinic acetylcholine receptors are different but homologous proteins," Proc. Natl. Acad. Sci. USA, 82:5208-5212 (1985).
Couturier et al., "A Neuronal Nicotinic Acetylcholine Receptor Subunit (.alpha.7) Is Developmentally Regulated and Forms a Homo-Oligomeric Channel Blocked by .alpha.-BTX," Neuron, 5:847-856 (1990).
Dascal, "The Use of Xenopus oocytes for the study of Ion Channels," CRC Critical Reviews in Biochemistry, 22:317-387 (1987).
Deneris et al., ".beta..sub.3 : A New Member of Nicotinic Acetylcholine Receptor Gene Family Is Expressed in Brain," The Journal of Biological Chemistry, 264:6268-6272 (1989).
Deneris et al., "Pharmacological and functional diversity of neuronal nicotinic acetylcholine receptors," TIPS, 12:34-40 (1991).
Deschamps et al., Identification of a Transcriptional Enhancer Element Upstream from the Proto-Oncogene fos, Science, 230:1174-1178 (1995).
Doolittle, OF URFS AND ORFS, University Science Books, Mill Valley,10-15 (1986).
Duvoisin et al., "The Functional Diversity of the Neuronal Nicotinic Acetylcholine Receptors Is Increased by a Novel Subunit: .beta.4," Neuron, 3:487-496 (1989).
Fornasari et al., "Molecular cloning of human neuronal nicotinic receptor .alpha..sub.3 -subunit," Neuroscience Letters, 111:351-356 (1990).
Goldman et al., "Members of a Nicotinic Acetylcholine Receptor Gene Family Are Expressed in Different Regions of the Mammalian Central Nervous System," Cell, 48:965-973 (1987).
Ishikawa et al., "Acetylcholine Receptors of Human Skeletal Muscle: a Species Difference Detected by Snake Neurotoxins," Brain Research, 346:82-88 (1985).
Kurosaki et al., "Functional properties of nicotinic acetylcholine receptor subunits expressed in various combinations," FEBS Letters, 214:253-258 (1987).
Larsson et al., "In vitro Binding of .sup.3 H-Acetylcholine to Nicotinic Receptors in Rodent and Human Brain," Journal of Neural Transmission, 69:3-18 (1987).
Lathe, "Synthetic Oligonucleotide Probes Deduced from Amino Acid Sequence Data," J. Mol. Biol. 183:1-12 (1985.
Luetje and Patrick, "Both .alpha.-and .beta.-subunits Contribute to the Agonist Sensitivity of Neuronal Nicotinic Acetylcholine Receptors," The Journal of Neuroscience, 11:837-845 (1991).
Lukas, "Pharmacological Distinctions between Functional Nicotinic Acetylcholine Receptors on the PC12 Rat Pheochromocytoma and the TE671 Human Medulloblastoma," The Journal of Pharmacology and Experimental Therapeutics 251:175-182 (1989).
Marshall et al., "Sequence and fun
Akong Michael
Brust Paul
Ellis Steven Bradley
Harpold Michael Miller
Velicelebi Gonul
SIBIA Neurosciences Inc.
Siedman Stephanie L.
Ulm John
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