Mammalian catecholamine receptor genes and uses

Details Mammalian catecholamine receptor genes and uses Mammalian catecholamine receptor genes and uses

2000-09-12

2004-08-31

Kemmerer, Elizabeth (Department: 1647)

Chemistry: molecular biology and microbiology

Micro-organism, per se ; compositions thereof; proces of...

Bacteria or actinomycetales; media therefor

C435S320100, C435S325000, C435S069100, C536S023500

Reexamination Certificate

active

06783973

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to catecholamine receptors from mammalian species and the genes corresponding to such receptors. Specifically, the invention relates to the isolation, cloning and sequencing of complementary DNA (cDNA) copies of messenger RNA (mRNA) encoding a novel mammalian catecholamine receptor gene. The invention also relates to the construction of recombinant expression constructs comprising cDNA of this novel catecholamine receptor gene, said recombinant expression constructs being capable of expressing catecholamine receptor protein in cultures of transformed prokaryotic and eukaryotic cells. Production of the receptor protein in such cultures is also provided. The invention relates to the use of such cultures of such transformed cells to produce homogeneous compositions of the novel catecholamine receptor protein. The invention also provides cultures of such cells producing this catecholamine receptor protein for the characterization of novel and useful drugs. Antibodies against and epitopes of this novel catecholamine receptor protein are also provided by the invention.
2. Background of the Invention
Catecholamines are a class of naturally-occurring amino acid derivatives having a variety of physiological effects in the peripheral and central nervous systems. The parent compound is &bgr;-phenylethylamine, and the catecholamines are derivatives of this parent compound. In addition to the naturally-occurring members of the class (epinephrine, norepinephrine and dopamine), a large number of synthetic compounds having biological activity have been developed and have utility as drugs (including albuterol, isoproterenol, propranolol, phenylephrine, amphetamine and methamphetamine). In the periphery, catecholamines are released by the sympathetic nervous system and adrenal medulla and are involved in integrating physiological responses to stress, while in the central nervous system the catecholamines constitute some of the most important neurotransmitter systems.
The effect of catecholamines are mediated through their receptors and their associated cell signaling systems (reviewed in Hoffman & Lefkowitz, 1982, Ann. Rev. Physiol. 44: 475-484; Civelli et al., 1993, Ann. Rev. Pharm. & Tox. 33: 281-307). These receptors are located in the plasma membrane of catecholamine-sensitive cells. Structurally, they are characterized by having a pattern of seven transmembrane domains (see,for example, U.S. Pat. Nos. 5,422,265,5,569,601, 5,594,108,5,883,226, 5,880,260,5,427,942 and 5,686,573). Functionally, certain of these receptors interact with adenylate cyclase, either stimulating or inhibiting the production of cyclic AMP thereby. These receptors include the adrenergic receptors (the a-1, a-2, b-1, b-2, and b-3 adrenergic receptors) and the dopamine receptors (the D
1
-, D
2
-, D
3
-, D-
4
-, and D
5
-dopamine receptors).
For example, epinephrine (adrenaline) and norepinephrine, as well as synthetic agonists of these catecholamines which mimic their biological functions, and antagonists which block these biological functions, exert their effects by binding to specific recognition sites (membrane receptors) situated on the cell membranes in the peripheral nervous system, Two principal classes of adrenergic receptors have been defined, the alpha-adrenergic receptors and the beta-adrenergic receptors. Five subtypes of adrenergic receptors ( a-1, a-2, b-1, b-2, and b-3 adrenergic receptors) have now been distinguished. The genes encoding these receptors have been isolated and identified (Cotecchia et al., 1988
, Proc. Natl. Acad. Sci. USA
85: 7159-7163; Kobilka et al., 1987
, Science
238: 650-656; Frielle et al., 1987
, Proc. Natl. Acad. Sci. USA
84: 7920-7924; Emorine et al., 1987
, Proc. Natl. Acad. Sci. USA
84: 6995-6999; Emorine et al., 1989
, Science
245: 1118-1121). Analysis of these genes has made it possible to recognize that they belong to a family of integral membrane receptors exhibiting some homology (Dixon et al., 1998, Annual Reports in Medicinal Chemistry, 221-223; Emorine et al., 1988
, Proc. NATO Adv. Res. Workshop
), especially at portions of the seven transmembrane regions that are coupled to regulatory proteins, called G proteins, capable of binding molecules of guanosine triphosphate (GTP).
These membrane receptors, after they have bound the appropriate ligand (agonist or antagonist), are understood to undergo a conformational change that induces an intracellular signal that modifies the behavior of the target cell. Beta-adrenergic receptors catalyze the activation of a class of G proteins which in turn stimulates the activity of adenylate cyclase when they bind with catecholamine agonists, whereas alpha-adrenergic receptor antagonists act in competition with the agonists for the binding to the receptor and prevent the activation of adenylate cyclase. When adenylate cyclase is activated, it catalyses the production of an intracellular mediator or second messenger, especially cyclic AMP.
In the central nervous system, dopamine is a catecholamine neurotransmitter modulates neuronal cells involved in movement initiation, appetitive behavior, hormone release, and visual dark adaptation. In the periphery dopamine plays a role in modulating blood pressure and renal function (see generally Cooper et al., 1978
, The Biochemical Basis of Neuropharmacology
, 3d ed., Oxford University Press, New York, pp, 161-195). The diverse physiological actions of dopamine are in turn mediated by its interaction with a family of distinct dopamine receptors subtypes that are either “D1-like” or “D2-like,” which respectively stimulate and inhibit the enzyme adenylate cyclase (Kebabian & Calne, 1979
, Nature
277: 93-96). Alterations in the number or activity of these receptors may be a contributory factor in disease states such as Parkinson's disease (a movement disorder) and schizophrenia (a behavioral disorder) and attention deficit hyperactivity disorder (ADHD).
A great deal of information has accumulated regarding the biochemistry of the D1 and D2 dopamine receptors, and methods have been developed to solubilize and purify these receptor proteins (see Senogles et al., 1986
, Biochemistry
25: 749-753; Sengoles et al., 1988
, J. Biol. Chem.
263: 18996-19002; Gingrich et al., 1988
, Biochemistry
27: 3907-3912). The D1 dopamine receptor in several tissues appears to be a glycosylated membrane protein of about 72 kD (Amlaiky et al., 1987
, Mol. Pharmacol
. 31: 129-134; Ninzik et al., 1988
, Biochemistry
27: 7594-7599). The D2 receptor can also be glycosylated and has been suggested to have a higher molecular weight of about 90-150 kD (Amlaiky & Caron, 1985
, J. Biol. Chem.
260: 1983-1986; Amlaiky & Caron, 1986
, J. Neurochem
. 47: 196-204; Jarvie et al., 1988
, Mol. Pharmacol
. 34: 91-97).
Dopamine receptors are primary targets in the clinical treatment of psycho-motor disorders such as Parkinson's disease and affective disorders such as schizophrenia (Seeman et al., 1987
, Neuropsychopharm
. 1: 5-15; Seeman, 1987
, Synapse
1: 152-333). Five different dopamine receptor genes (D1, D2, D3, D4 and D5) and various splice variants of their transcripts have been cloned as a result of nucleotide sequence homology which exists between these receptor genes (Bunzow et al., 1988
, Nature
336: 783-787; Grandy et al., 1989
, Proc. Natl. Acad. Sci. USA
86: 9762-9766; Dal Toso et al., 1989
, EMBO J
. 8: 4025-4034; Zhou et al., 1990
, Nature
346: 76-80; Sunahara et al., 1990
, Nature
346: 80-83; Sokoloff et al., 1990
, Nature
347: 146-151; Civelli et al., 1993
, Annu. Rev. Pharmacol. Toxicol
. 33: 281-307; Van Tol et al., 1991
, Nature
350: 610-4).
Catecholamine receptors are also targets for a host of therapeutic agents for the treatment of shock, hypertension, arrhythmias, asthma, migraine headache, and anaphylactic reactions, and include antipsychotic drugs that are use to treat schizophrenia and &bgr;-blockers used to control high blood pressure.
The importance of catecholamine receptors, particularly in the brain and

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